This document is dedicated to the memory of our friend and colleague Lloyd Mayer, MD (1952-2013), whose vision, intelligence, dedication, and collegiality, were essential for the development of immunology at Mount Sinai.

The Immunology Institute of Mount Sinai School of Medicine was established in February of 2007. The main mission of the Immunology Institute is to foster research, collaboration, and education in immunology. The team The Institute is led by Sergio Lira and is home to 42 basic scientists and clinicians (Appendix V). The programs Immunology Institute investigators study the physiology and pathophysiology of immune cells with a special emphasis on the mechanisms of disease pathogenesis, and development of therapeutic interventions. Our main programmatic areas are Mucosal Immunology, Immunodeficiencies, Food Allergy, Immunomonitoring and Immunotherapy. Our basic and clinical researchers collaborate extensively. We have unique patient populations who give us an advantage in terms of translational science. Where we do not have direct access to human samples, animal models of disease are created. This melding of patient populations with animal models and multiple approaches to study mechanisms is unique and serves to distinguish the Immunology Institute from other Immunology programs around the country. In our institute, faculty with interest in diverse aspects of the immune system work together to achieve excellence in research, mentoring, and training.

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Mucosal Immunology Mount Sinai and IBD have been synonymous since 1932 when the initial description of Crohn’s disease was made at Mount Sinai. There is a strong base of clinical and basic research and probably one of the largest patient populations in the world. This access to patients allows us to perform unique studies looking at the control of mucosal inflammation (Colombel, Lira, Blander, Yeretssian, Esplugues, Mehandru, Cerutti), lymphocyte/ epithelial cell interactions (Dahan, Berin, and Lira) and the microbiome (Lira, Colombel, Faith, Clemente, Furtado, Merad, Alexandropoulos, Cerutti). Our investigators study the ontogeny and composition of mucosal immune cell populations (Merad, Alexandropoulos), cellular migration (Lira, Furtado, Esplugues), signaling (Ting, Chen, Xiong, Yeretssian), apoptosis and necrosis (Blander, Ting, Yeretssian). In the area of immunoregulation, we study the function of specific suppressor or regulatory pathways (Chen), role of complement in T cell function and transplantation (Heeger) and the role of microRNAs in immune cell function (Brown). These are emphasized translationally by several human disorders. Funding for the mucosal immunology program has been provided by a program grant in innate and adaptive immunity in IBD (Lira, Blander, Xiong, Ting), several RO1s, and a generous gift from the Helmsley Foundation that has allowed us to further recruit into the Institute (Cerutti, Espluges, Yeretssian, Faith) and establish a germ-free animal facility for studies on the microbiome.

Immunodeficiency Our investigators focus on basic aspects of B cell function (Cortes, Cerutti, Cunningham-Rundles), and we have an outstanding clinic in Primary Immunodeficiency. Charlotte Cunningham-Rundles runs the largest Primary Immunodeficiency clinic in the Northeast and possibily the US. In addition to a program grant and several RO1s, there are several ongoing clinical trials. Food allergy Hugh Sampson runs the pediatric food allergy clinic, although some adults are seen as well. Clinical research, clinical trials, and basic research are all ongoing and well funded. Cecilia Berin studies the role of physiologic or environmental adjuvants that may promote the development of allergic sensitization by altering the phenotype of mucosal dendritic cells and Paula Busse studies mechanisms of allergies in older populations. XiuMin Li and Madhan Masilamani study immunopathogenic mechanisms underlying food allergy and novel therapies for these allergic diseases. The results of these efforts are a wellfunded program in food allergy (Sampson and Berin). Human Immune Monitoring Center A recent effort spearheaded by Miriam Merad and Sacha Gnjatic, focus on the development of platforms to evaluate the immune system in health and disease. State-of-the-art technologies (mass cytometry, seromics, TCR sequencing) are being implemented to assess the immune system in patients receiving different therapy modalities. Immunotherapy 3

Our efforts in immunotherapy originate from the pioneering work done by Lloyd Mayer and Charlotte-Cunningham Rundles, who first applied biologicals to the treatment of immunodeficiencies and inflammatory bowel disease at Sinai. This work expanded into the treatment of other immune-based diseases, with polyclonal and monoclonal antibodies, cytokines and fusion proteins. Subsequent work by Hugh Sampson and his team has focused on development of novel therapeutic modalities for food allergy. A major effort in this area is underway. More recently, a major effort in cancer immunotherapy has been launched by Steven Burakoff at the Tisch Cancer Center, who has recruited Nina Bhardwaj to lead the cancer immunotherapy program. The Center of Therapeutic Antibody Development led by Tom Moran produces human monoclonal antibodies using both mouse models and human cells and is an important resource available for the immunology community. A detailed description of our programs is found within this document. Science productivity Scientists form the Immunology Institute and their groups have published 622 papers in the period 2007-2014. Many of these papers appeared in high impact journals (Nature, Cell, Science, Nature Immunology, Immunity, JEM, JCI, JACI). A list of papers published since 2013 is found in the Appendix I.

Funding Members of the Immunology Institute (33 out of 42 faculty) raise approximately US$ 34 million dollars in direct funds yearly. Most of these funds originate from NIH grants and contracts (US$ 21 million). Grants form pharmaceutical sector (US$ 4 million) and foundations (US$ 9 million) also support our scientists. Physical space The Immunology Institute members are located throughout the Icahn School of Medicine campus and occupy 36,488 sq ft of wet lab space ( 868 sq ft/investigator). Resources Several Shared Research Facilities are available to our community including Imaging, Mouse Genetics, Genomic Cores and the Immunomonitoring Center. Interaction with other Institutes/Clinical divisions Interactive programs are carried out by several labs in the Institute with the members of the Transplant Institute and with the Diabetes, Obesity and Metabolism Institute. Examples include research in thyroid autoimmune disease (Davies, Tomer) and in Type I diabetes (Tomer, Brown) and transplantation (Murphy, Heeger, Ochando). Basic mechanisms of autoimmunity and transplant biology such as central mechanisms of T cell selection (Alexandropoulos) and mechanisms of tolerance (Ochando, Heeger) are being explored. We have developed a joint exploratory program in neuroinflammation with the Friedman Brain Institute and these 4

interactions have led to a recently funded NIH application (Russo, Merad). Our scientists participate in collaborative programs with scientists and clinicians at the Tisch Cancer Center, at the Icahn Institute for Genomic Sciences, and in the Department of Medicine (Divisions of Clinical Immunology, Gastroenterology, Rheumatology, and Dermatology). The focus of study in most cases is the role of inflammation in many disease processes. An excellent example of this is a joint project supported by Janssen Pharmaceuticals on the mechanisms underlying the development of inflammatory bowel disease. This involves immunologists (Lira, Xiong, Dahan), gastroenterologists (Colombel, Sands), geneticists (Cho) and computational biologists (Schadt, Kasarskis). Other efforts involving the study of rheumatoid arthritis (Gulko) and dermatological disorders (Guttman) are underway. Education With the establishment of the Institute, we created a MD/PhD and PhD program in Immunology. Our scientists and their trainees meet weekly and discuss their findings at the Work-inprogress Seminar Series. Once a month, we host internationally renowned immunologists at the Immunology Seminar Series, and once a year, we hold an Institute retreat to bring together all of the laboratories. The goal remains to promote a highly interactive productive environment for the training of graduate students, postdoctoral fellows, junior, and senior faculty. Our recruitments over the past 7 years have already reaped benefits in terms of creating a sense of community and an interactive training environment. Our Work-in-progress meetings have fostered collaborations that led to project grants. Both the

immunodeficiency PPG and mucosal immunology/IBD PPG arose from these meetings. They have also solidified Immunology as a distinct entity that is easily recognized by students and postdoctoral fellows as a desirable area for training. Recruitment of students has increased tremendously, with the pool of applicants doubling in the last years. Furthermore, we have had a training grant for over 8 years that funds postdoctoral fellows and graduate students. In addition to our graduate program, that focuses on the training of PhDs and

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MSTP students, our faculty maintains a strong commitment to the mentoring of medical students, residents, and clinical fellows. Immunology Institute website General and relevant information of the weekly activities of the Institute can be found at our website: http://www.iisinai.org/

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Mucosal Immunology

The Mucosal Immunology program at Mount Sinai began with Dr. Lloyd Mayer, who continued a long-standing tradition of excellence in studies pertaining to inflammatory bowel disease (IBD). This tradition started in 1932, when Dr. Burrill Crohn first described Crohn’s disease. The program expanded in 2007, when Dr. Sergio Lira and Dr. Mayer were named co-Directors of the Immunology Institute. After receiving a Hemsley Trust Grant in 2009, Mount Sinai expanded a pre-existing roster of internationally recognized immunologists by recruiting four new faculty members, including Drs. Andrea Cerutti, Garabet Yeretssian, Enric Esplugues and Jeremiah Faith. Goals The Mucosal Immunology program has the following general goals. 1) To make breakthroughs in our understanding of the intertwined biological networks mediating gut homeostasis, including the immune system, epithelium, mucus and microbiota. 2) To make major advances in our understanding of IBD by taking advantage of fundamental discoveries in the regulation of gut homeostasis. 3) To translate advances in basic biology into more effective therapies for IBD. The complementary expertise and highly collaborative nature of our team is ideally suited to “crack” the inflammatory codes underpinning IBD and to generate “out-of-the-box” ideas for more effective therapies.

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Team The labs of Drs. Blander, Cerutti, Merad, Lira, Furtado, Xiong, Berin, Mehandru, Esplugues, Faith, Yeretssian and Ting do basic research in mucosal immunology. We have a strong collaborative program with the Helmsley IBD Center at Sinai. In addition, the Immunology Institute is home to members of the IBD center, such as Drs. Colombel and Cho, who conduct clinical research and genetic studies in IBD populations. Themes Ontogeny, trafficking, and function of mucosal immune cells. The Merad group studies the biology of the mononuclear phagocyte system. They have identified distinct precursors of tissue macrophages under steady-state conditions and inflammation, completely revising the existing paradigms. This group also identified ontogenetically distinct subsets of mucosal dendritic cells (DCs). Ongoing studies are aimed at exploring the contribution of individual DC and macrophage subsets to IBD. The Lira group studies how chemokines regulate the homeostatic and inflammatory influx of specific leukocytes into the intestine and how chemokines regulate the development and maintenance of gut lymphoid structures. Ongoing studies are evaluating the role of individual chemokines in different disease settings, Including IBD. The Merad and Brown groups have collaborated to dissect the transcriptional networks and microRNAs that regulate the development and tolerogenic function of mucosal DCs and macrophages under steady-state conditions and after immunization. The Merad group has identified GM-CSF as a tissue-specific regulator of DCs and macrophages. Their groups jointly evaluate the transcriptional and microRNA profiles of

DCs in IBD and aim to identify novel therapeutic targets along the GM-CSF and miR-126 axis. The Blander group identified prokaryotic messenger RNA as a prototype “vita-PAMP” recognized by the TLR adaptor TRIF along with the NLRP3 inflammasome. Ongoing work is defining the innate and adaptive pathways mobilized by live bacteria to generate more effective vaccines. This group also showed that Rab11a stocks the endosomal recycling compartment (ERC) in DCs with MHC-I. TLRs control MHC-I delivery from ERC to phagosomes via MyD88-IKK2 phosphorylation of SNARE SNAP23. In this way, selective MHC-I recruitment to phagosomes containing TLR ligands favors those phagosomes for cross-presentation. The Cerutti group elucidated how BAFF and APRIL from mucosal DCs activate class switching and IgA production in mucosal B cells through the TACI receptor. These studies involved extensive collaborations with Dr. Charlotte Cunningham-Rundles from the Immunodeficiency Program and led to the identification of TACI interaction with the TLR adaptor MyD88 and to the development of a collaborative program (PPG). Additional collaborations with Drs. Lira, Merad and Blander focus on the role of TACI and its homologue BCMA in gut homeostasis and inflammation. The Cerutti group also elucidated the mechanism by which mucosal B cells switch from IgM to IgD to establish a crosstalk with IL-4-producing basophils. Ongoing collaborations with the Allergy Program including Drs. Sampson and Berin, aim at defining the role of IgD in mucosal homeostasis and inflammation, including allergy. The biology of Ig gene diversification in B cells is also tackled by Dr. Cortes. Interplay between mucosal immune cells, mucus and the microbiota. The Cerutti group, in collaboration with Dr. 8

Blander, found that the microbiota inhabits a mucus niche that establishes a functional interplay with the gut immune system. Indeed, the gut-specific mucin MUC2 interacts with luminal bacteria and constraints their immunogenicity by providing regulatory signals to antigen-sampling DCs. Current collaborations with Drs. Merad, Lira, Sampson and Berin are evaluating the perturbations and anti-inflammatory potential of MUC2 in IBD. The Lira group studies the contribution of the microbiota to the development of IBD and cancer. Recent work shows that host and site-specific microbiota controls the development of neoplasia in genetically susceptible mice. These studies were done in close collaboration with the Merad, Faith and Clemente groups. The Faith group studies how diet affects the microbiome. They found that diet predictably controls the relative abundance of gut microbes and that the majority of gut strains in healthy individuals remain stable throughout life. The Faith group also developed a systematic and unbiased platform to identify the microbial strain or group of strains that modulate key aspects of mucosal immunology, with the goal of generating next generation probiotic combinations for treating IBD. Current studies in the Faith lab investigate the stability of the gut microbiota in individuals with IBD and the extent to which microbiota stability can serve as a predictive indicator of disease onset and progression. Additional studies aim at implementing dietary interventions to modulate the pathogenesis of IBD. The Faith group actively interacts with clinicians at the IBD center. Regulation of mucosal inflammation by cytokines. The Merad group found that GM-CSF-producing ILCs inhibit gut inflammation by stimulating the production of tolerogenic factors such as retinoic acid in gut DCs. In the absence of GM-

CSF, gut DCs become less competent to promote the formation of Treg cells with anti-inflammatory activity, which predisposes to inflammation. Ongoing studies in collaboration with Drs Cho and Colombel (IBD center) evaluate the pathogenetic role of antibodies to GM-CSF and polymorphisms of the gene encoding GM-CSF during IBD. The Cerutti group identified mucosa-like ILCs that activate splenic MZ B cells through a GM-CSF-regulated pathway involving neutrophils. Studies on marginal zone (MZ) B cells involved collaborations with Drs. Blander, Merad, Xiong, and Cunningham-Rundles. Ongoing studies in collaboration with Dr. Merad are deciphering how a dysregulation of this pathway may hamper antibody responses to capsular polysaccharides during IBD. The Blander group showed that infection and apoptosis coinduce inflammatory and anti-inflammatory cytokines critical for TH17 responses. These findings set the stage for defining the antigenic specificity of TH17 cells and open new avenues for a better understanding of TH17 cell responses during IBD. Studies on trafficking and function of mucosal Th17 cells are also developed by Drs. Esplugues, Xiong and Ting. The Lira group was the first to show that IL-23 promotes inflammation through pathways previously attributed to IL-12. Their current studies evaluate how IL-23 modulates ILCs to regulate mucosal immunity and inflammation. Achievements •

A program project grant (PPG) on mucosal immunology. The present members of this grant are Drs. Lira (PI), Blander, Ting and Xiong. This grant allowed for the generation of several collaborations within the Institute, the development

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•

•

•

of a pathology core (under Dr. Harpaz), and a mouse genetics core (under Dr. Lira). These cores provide for access to pathological analyses and access to engineered mouse models. A grant from the Helmsley Trust, which has allowed for recruitment of new faculty (Cerutti, Faith, Esplugues, Yeretssian). This grant also established the Helmsley IBD center and the recruitment of outstanding gastroenterologists (Colombel) and geneticists (Cho), have joined the Institute and contributed to development of joint programs with the basic immunologists. This has led to joint programs such as SUCCESS (supported by philanthropy) and a program with Janssen Pharmaceuticals. The establishment of a microbiome program and the development of a germ-free facility (under Dr. Faith) that will be critical for stuies involving the microbiome. Publications in major scientific journals (Cell, Nature, Science, Nature Immunology, Immunity, J. Exp. Med., JCI, etc)

Future Gut homeostasis and IBD involve intertwined biological networks that include the immune system, epithelium, mucus and microbiota. Our core team includes investigators highly recognized in the fields of DCs, macrophages, microbial sensing, B cells, chemokines and microbiota. To optimize our program and uncover how complex mucosal biological networks deviate toward inflammation in response to both environmental and genetic factors we envision: •

Recruitment of experts in epithelial cell biology, microbiology, metabolomics and glycobiology. In particular we consider the area of glycobiology an area of growth in mucosal biology. Mucus contains hyperglycosylated mucins

•

that anchor and regulate the composition of the microbiota. Conversely, the microbiota stimulates mucin production to generate energy and growth signals from mucin-associated glycans. Of note, perturbations of mucin glycosylation brought about by primary or acquired alterations of specific glycosyla transferases (e.g., FUT2) play an important role in the pathogenesis of IBD. These alterations may alter the composition of the microbiota and the generation of tolerogenic DCs. We believe that defining the glycobiome of individual IBD patients may have both biological and clinical (i.e., predictive) values. Better integration with bioinformaticians at the Genomic Institute to facilitate the analysis of data emerging from

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•

•

transcriptome, microbiome, metabolome, and glycobiome studies. Support for studies centering on human mucosal immunology. We consider support of the Immunomonitoring Center and creation of a tissue repository for the collection, storage and distribution of mucosal samples as important factors for the improvement of existing interactions of basic scientists with our clinicians. Wide dissemination of novel technologies, including CRISPR/Cas, Mass Cytometry and Seromics to the study of mucosal immunology/IBD. These technologies are currently spearheaded by Drs. Sergio Lira, Brian Brown and the Immunomonitoring Center.

Andrea Cerutti graduated in Medicine and specialized in Hematology at Padua University, Italy. After completing a postdoctoral fellowship in immunology he was appointed Assistant Professor (2001) and Associate Professor (2006) of Pathology at Weill Medical College of Cornell University. He joined the Immunology Institute of Icahn School of Medicine at Mount Sinai in 2010 as Professor of Medicine. Dr. Cerutti is a member of the Henry Kunkel Society and the American Society for Clinical Investigation, and co-organized two Keystone Symposia meetings on B cells.

and homeostasis and the mechanisms by which mucosal IgD regulates immunity and inflammation, including allergy. IgA-interacting mucins and gut homeostasis

Research Interests

We take advantage of both mouse and human models to explore the function of the IgA-interacting mucin MUC2 in gut homeostasis. We found that MUC2 constraints the immunogenicity of gut antigens by providing regulatory signals to antigen-sampling dendritic cells through a receptor complex involving Dectin-1, FcgammaRIIB and galectin-3. Our studies highlight a close interplay between MUC2-secreting goblet cells and the gut immune system and suggest that mucus actively delivers anti-inflammatory signals in addition to forming a physical barrier. The role of MUC2 in inflammatory bowel disease is under evaluation.

IgA and IgD production by mucosal B cells

IgM, IgG and IgA production by splenic B cells

We use both mouse and human models to gain new insights into the biology of IgA and IgD, two antibody classes released by intestinal and respiratory B cells, respectively. We have shown that mucosal dendritic cells and epithelial cells enhance IgA production by releasing BAFF and APRIL (NI, 2002; Immunity, 2007; NI 2009), two class switch-inducing TNF family members that activate a TLR-like pathway involving the TACI receptor on B cells (NI, 2010). We have also found that HIV alters mucosal IgA production by interfering with signals from CD40L, a TNF family member expressed by T cells (NI, 2006; NI 2009). Finally, we have demonstrated that a unique subset of mucosal B cells switches from IgM to IgD to establish a crosstalk with IL-4producing basophils (NI, 2009). We currently study the role of TACI and BCMA (another BAFF/APRIL receptor) in gut immunity

We use mouse, rhesus macaque and human models to better understand the biology of marginal zone (MZ) B cells, an innatelike B cell subset involved in rapid antibody responses to bloodborne viral and bacterial carbohydrate antigens. We recently found that MZ B cells receive BAFF and APRIL helper signals from neutrophils (NI 2011). We also identified a new subset of splenic innate lymphoid cells (ILCs) that have mucosa-like properties and release the neutrophil-activating cytokine GMCSF (NI 2014). We are currently deciphering the stromal and immunological signals that regulate the activation of splenic ILCs, the relationship of splenic ILCs with the gut, and the relevance of splenic ILCs and GM-CSF to protective antibody responses against HIV and encapsulated bacteria.

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Sergio Lira received his MD from the Universidade Federal de Pernambuco in Brazil and his PhD in Physiology and Pharmacology from the University of California at San Diego. He did his postdoctoral training at the Roche Institute for Molecular Biology in Nutley, NJ. After his postdoctoral training he worked for 11 years in the pharmaceutical industry, first at BristolMyers Squibb and then at Schering-Plough. He is currently the The Leona M. and Harry B. Hemsley Charitable Trust Professor of Immunology at the Icahn School of Medicine at Mount Sinai in New York, where he is the Director of the Immunology Institute. He has organized international meetings in this field, including the 2003 Keystone Symposium on Chemokines, the 2006 Gordon Research Conference on Chemotactic Cytokines, and the 2012 Keystone Symposium on Chemokines and Leukocyte trafficking. He was elected to the Henry Kunkel Society in 2006 and to the Association of American Physicians in 2008. He is a member of the Board of Scientific Advisors of the National Cancer Institute and Visiting Professor at the Southern Medical School in Guangzhou, China.

to the intestine. We have shown that chemokines regulate the homeostatic and inflammatory influx of leukocytes into the intestine and that they are important for the development and maintenance of lymphoid structures in the intestine (MI, 2009, 2010, 2014; JCI, 2011, Immunity 2013)

Research Interests

Role of genetic variants in the development of IBD

Regulation of leukocyte trafficking into the intestine during homeostatic and pathologic conditions

We are using CRISPR technology to generate mouse mutants carrying SNPS associated with IBD. We expect to learn how these genetic variants increase risk or protect humans from IBD.

Our lab uses genetic approaches to study the role of chemokines and their receptors in the migration of specific leukocyte subsets

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Role of IL-23 in mucosal inflammation Studies done by our lab were the first to show that IL-23 expression promotes inflammation (JI, 2000). In collaboration with Cua and Kastelein we also showed that many of the inflammatory phenotypes previously attributed to IL12 were in fact driven by IL-23 (Nature, 2002). We currently study the role of IL-23 in mucosal immunity, focusing on its ability to promote development of innate lymphoid cells. Role of the microbiota in mucosal inflammation and cancer Our lab studies the contribution of the microbiota to the development of inflammatory bowel diseases and cancer. Our recent work suggests that host and site-specific microbiota is important for development of neoplasia in genetically susceptible mice (JEM, 2014).

Jeremiah Faith received his PhD in Bioinformatics and Systems Biology from Boston University. He did his postdoctoral training in the laboratory of Jeffrey Gordon at Washington University in St. Louis Medical School with a focus on the structure and function of the gut microbiome in healthy individuals. He is currently an Assistant Professor in the Immunology Institute and the Institute for Genomics and Multiscale Biology in the Icahn School of Medicine at Mount Sinai in New York. His research focuses on modeling the interactions between diet, gut microbes, and host physiology with an emphasis on Inflammatory Bowel Disease. Research Interests Quantifying the influence of diet and the gut microbiota on host health and disease Using gnotobiotic mice harboring a defined collection of human gut microbes and systematic dietary perturbations, we found the abundances of gut microbes can be predictably controlled with diet. We are currently using these results to implement dietary interventions that modulate pathogenesis in mouse models of colitis. Using a combination of dietary manipulations and gnotobiotic animals, we are quantifying the individual contributions of diet and the microbiota on disease

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pathogenesis as well as synergistic interactions between these two key environmental parameters that influence health. Identifying microbial strains that modulate host phenotypic variation Microbiome studies to understand the role of our gut microbes in health and disease have largely been descriptive in nature or have focused on identifying a stain capable of modulating a property of host physiology. By combining high throughput culturing methods with a gnotobiotic-screening pipeline, we developed a systematic, unbiased platform to identify the strain or group of strains in a microbiota that confers a phenotype of interest on the host. We are apply this technology to identify microbes that modulate aspects of mucosal immunology and inflammatory diseases with the goal of generating next generation probiotic combinations for treating human disease. The stability of the human gut microbiota The gastrointestinal tract harbors roughly 100 different species of bacteria that are unique to each individual. Despite numerous daily encounters with a microbe-rich world, we found that the majority of strains in healthy individuals remain stably colonized throughout life. We are currently investigating the stability of the gut microbiota in individuals with disease and the extent to which microbiota stability can serve as a predictive indicator of disease onset and progression.

Miriam Merad was trained as an Oncologist in Paris, France and obtained her PhD in Immunology from University Paris VII and Stanford University in 2001. She was recruited to the Icahn School of Medicine at Mount Sinai School in 2004 and was promoted to the rank of Associate Professor with Tenure in 2007, and to Full Professor in 2010. Dr. Merad serves as the Co-Leader of the Cancer Immunology Program at the Tisch Cancer Institute and the Associate Director for the M.D.; Ph.D. program at Mount Sinai Medical School. Dr. Merad’s laboratory studies the mechanisms that regulate the development and function of innate myeloid cells including dendritic cells, Langerhans cells and macrophages. In 2013, Dr. Merad was the primary organizer of the Keystone conference on dendritic cell biology and was elected to the “American Society of Clinical Investigation”. She has authored more than 100 primary papers and review articles in high profile journals and obtained extensive NIH funding for her studies on dendritic cells and macrophage biology in mice and humans. Dr. Merad leads the Human Immunomonitoring Center, which provides cutting edge technology for comprehensive analysis of the human immune system. Research interests Regulation of macrophage development and function

and

dendritic

cell

(DC)

In contrast to the dogma that most macrophages derive from circulating monocytes, we have showed that most tissue

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resident macrophages arise from embryonic precursors that take residence in tissues prior to birth, where inflammatory macrophages mostly derive from circulating monocytes (Merad et al. Nature Immunology 2002; Ginhoux et al. Nature Immunology 2006; Ginhoux et al. Science 2010; Hoeffel et al. JEM 2012; Hashimoto et al.; Immunity 2013). We are currently deciphering the contribution of these distinct macrophage lineages to disease pathogenesis. In contrast to macropahges, tissue DC arise from adult bone marrow precursors along two distinct developmental pathways (Ginhoux et al, JEM 2009; Bogunovic et al. Immunity 2009; Helft et al. JCI 2012). We are currently examining the contribution of distinct DC subsets to tissue integrity and to antimicrobial and antitumor immunity. Maintenance of Mucosal Tissue Integrity One of the focus of our laboratory in the recent years has been the identification of tissue-derived factors that contribute to survival and function of macrophage and DC in barrier tissues. Work in this area includes the characterization of IL-34 as a critical factor controlling development of Langerhans cells and microglia (Greter et al, Immunity 2012). We have also shown that that GM-CSF is produced by gut tissue resident innate lymphocytes in response to commensal microbial signals to instruct macrophage and DC regulatory function and promote Treg homeostasis in the steady state (Mortha et al. Science 2014). More recently we uncovered a neuronal-macrophage crosstalk required to maintain intestinal motility (Muller et al. Cell, in press). In addition to gut tissue macrophages, we study the regulation of the development and function of tissue resident phagocytes in other barrier tissues including the skin and lung.

Brian Brown received his PhD in Pathology and Molecular Medicine from Queen’s University in Canada. He conducted his postdoctoral training at the San Raffaele Scientific Institute in Milan, Italy under the supervision of Dr. Luigi Naldini and Maria Grazia Roncarolo. He became faculty at Mount Sinai in 2008, and is currently an Associate Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York, as well as a faculty member in Mount Sinai’s Immunology Institute.

Molecular regulation of dendritic cells

Research Interests

microRNA biology

Immune tolerance

Dr. Brown’s lab is studying some of the fundamental principles of microRNA biology. His lab has been at the forefront of defining the stoichiometric relationship between microRNA and target concentration. They were one of the first to show that overexpression of a microRNA’s target can lead to ‘sponging’ of the microRNA. This work has had far-reaching implications for understanding the basic mechanisms of microRNA biology and for interpreting virtually all microRNA profiling data. It also helped lead to the development by his lab, and others, of microRNA sponge and decoy vector technology. His lab is continuing to investigate the relationship between microRNA concentration and target regulation, and to identify the posttranscriptional mechanisms that control microRNA activity.

One of the main goals of Dr. Brown’s lab is to develop strategies aimed at modulating the host immune response for inducing antigen-specific tolerance or immunity. Dr. Brown developed the first microRNA-regulated vector system. This is a new approach for targeting the expression of transgenes, vectors and viruses that has now been used by numerous labs for a range of emerging therapies ranging from gene therapy to oncolytic viruses. The first system he developed utilized target sites for the pan-hematopoietic microRNA, miR-142, to de-target antigen expression from macrophages and DCs. This enabled him to prevent an immune response to the antigen and even induce antigen-specific regulatory T cells. Dr. Brown’s lab is evaluating microRNA-based targeting as a means of inducing tolerance to islet antigens and prevent or reverse the development of type I diabetes.

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Dr. Brown is also working to understand the molecular regulation of dendritic cells. In collaboration with Dr. Miriam Merad in the Immunology Institute, Dr. Brown is carrying out work to decipher the transcriptional programs that control dendritic cell development and function. Recently, his lab identified a new pathway controlling the type I interferon response to pathogen-associated nucleic acids and HIV, which involves the microRNA miR-126, and the main VEGF receptor, VEGFR2. They are now investigating how the miR-126-VEGFR2 axis’s control of the innate immune system impacts melanoma growth.

Julie Magarian Blander received her Ph.D. from the University of Pittsburgh studying tumor immunology and immunotherapy under the mentorship of Olivera Finn. She conducted her postdoctoral training with Charles Janeway and Ruslan Medzhitov at Yale University pioneering the study of the impact of Toll-like receptors on macrophage and dendritic cell function. Dr. Blander is currently an Associate Professor with tenure at the Icahn School of Medicine at Mount Sinai. She is a 2014 Leukemia and Lymphoma Society Scholar, 2011 Burroughs Wellcome Fund Investigator, recipient of the 2009 G. Jeannette Thorbecke award, 2010 Lamport award, 2011 MSSM Faculty Council Junior Faculty Award for Academic Excellence, 2008 American Cancer Society scholar, and a 2007 Searle scholar. Her research interests center on the mechanisms of innate immunity and their impact on adaptive immunity.

Demonstrated that the innate immune system specifically detects and uniquely responds to microbial viability. We coined the term ‘vita-PAMPs’ uniquely associated with viable microorganisms, and identified prokaryotic messenger RNA as a prototype vita-PAMP via the Toll-like receptor (TLR) adaptor TRIF and the NLRP3 inflammasome. Addition of prokaryotic RNA to a dead vaccine augments its performance to that of a live vaccine. Our work here continues to define the innate and adaptive pathways mobilized by live bacteria, and their exploitation for new vaccines.

Research Interests

Discovered a major reserve of MHC class I (MHC-I) molecules in endosomal recycling compartment (ERC) of dendritic cells, mobilized with TLR signals and critical for crosspresentation. We showed that the small GTPase, Rab11a, stocks the ERC in dendritic cells with MHC-I. TLRs control MHC-I delivery from ERC to phagosomes via MyD88-IKK2 phosphorylation of SNARE SNAP23, leading to stable transSNAREs connecting ERC to phagosomes. Together with TLRindependent recruitment of the MHC-I peptide-loading complex from ER-Golgi intermediate compartments, selective MHC-I recruitment to phagosomes containing TLR ligands favors those phagosomes for cross-presentation.

Defined a physiological trigger for differentiation of TH17 cells. We showed that infection and apoptosis form a unique inflammatory signal that induces a combination of inflammatory and anti-inflammatory cytokines critical for a TH17 response. These findings demonstrated coexistence of immunosuppressive apoptosis with infection, and set the stage for defining the antigen specificities of TH17 cells. Because of strong associations between TH17 cells and autoimmune disease, the potential for developing autoreactive TH17 cells in this setting is a particular focus.

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Established the first dual targeting of Toll-like and Nod-like receptors for tumor immunotherapy. We designed a tumor cell vaccination approach whereby bacterial flagellin is expressed within tumor cells to synergistically target TLRs and NLRs and mount an effective anti-tumor adaptive response. These findings urge a reconsideration of the manner in which TLR ligands are used in tumor immunotherapy, and the necessity for the inclusion of NLR ligands for improved clinical outcomes.

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Allergy

The

Jaffe Food Allergy Institute was created with an

endowment from the Jaffe Family Trust in July 1997 with the goal of establishing an internationally recognized center for the study of food allergic disorders in children known for excellence in research, patient care and education. Dr. Hugh Sampson moved from Johns Hopkins with two junior faculty recruits, Dr. Scott Sicherer and Dr. Xiu-Min Li, a research nurse coordinator, Ms. Sally Noone, and a post-doctoral fellow, Dr. Kirsten Beyer. From this original group of 5 individuals, the Institute has expanded to over 60 members including 9 MD faculty, 3 PhD faculty, 6 research nurse coordinators, laboratory technicians, administrators and post-doctoral fellows. The Institute also hosts 1 – 2 visiting scientists from abroad each year. In the Jaffe Institute clinics, the medical faculty sees greater than 6,000 patient visits per year, providing a rich resource for over a dozen translational research studies conducted by Institute members. Central to the diagnosis and management of food allergies is a better understanding of oral tolerance and the underlying immunopathogenic mechanisms involved in allergic reactions. In recent years a variety of clinical trials have been launched for the treatment of milk, egg, peanut and wheat allergies using a variety of immunotherapeutic approaches including oral, sublingual and epicutaneous immunotherapy, and the use of a novel engineered recombinant peanut protein delivered rectally in E coli. While the latter approach proved extremely effective in a murine model of peanut allergy, Phase I clinical trials in man revealed more significant adverse allergic symptoms than anticipated. As outlined below, these clinical studies have been accompanied by basic immunologic studies attempting to better understand the immunopathogenesis of

18

food allergic disorders and changes in basic immune responses secondary to various immunotherapeutic approaches. Goal To help those with food allergies live safer and healthier lives through comprehensive care, education, and innovative research to find a cure.” Team Sampson Lab Dr. Sampson’s laboratory, which has been continuously funded by the NIH and various foundations, has focused on a number of areas related to food allergy. Early studies involved the development of murine models of food-induced anaphylaxis, which developed markedly elevated levels of food-specific IgE and experienced anaphylactic symptoms when fed the food allergens. In addition to studying basic immunologic mechanisms of food allergic reactions, these models were used to develop a number of therapeutic approaches to treat food allergy, including an engineered recombinant peanut protein vaccine, an herbal formulation for treating food allergy, and more recently a nanoparticle-based and DNA-plasmid chimerabased peanut vaccines. The Lab has also focused on the identification of major allergenic proteins within foods and has generated a repository of food protein cDNA’s that can be used for generating recombinant proteins for diagnostic tests and therapeutic vaccines. A focus on the interaction between IgE molecules, food proteins and clinical reactivity led to the finding that about 80% of young children with milk or egg allergy generate IgE antibodies

primarily to conformational epitopes and therefore can tolerate heat-denatured milk/egg proteins, and that introduction of these heat-denatured proteins into the diets of milk/egg allergic children accelerates the development of full tolerance. A number of basic mechanistic studies have been conducted to better understand the role of Treg cells and Th2 and effector cell (mast cells and basophils) suppression in the acquisition of clinical desensitization and tolerance. Using a novel peptide-based microarray developed by the Lab team, work over the last several years has shown the correlation between clinical reactivity, persistent clinical allergy and severity with patient IgE antibody binding to specific sequential epitopes on major food allergenic proteins. These studies have led to the development of a high through-put Luminex-based assay that is being developed in collaboration with Genisphere®. Recent studies also suggest that early monitoring of IgE and IgG4 epitope specific antibody responses will enabled physicians to better implement and administer oral immunotherapy. Li Lab Dr. Li and her team have focused on developing novel therapies including traditional Chinese medicines for food allergy and asthma, and the basic immunologic effects of these preparations. One project involves the development of a Chinese herbal medicine formula, FAHF-2 (food allergy herbal formula 2) for treating food allergies. Through NIH grants and foundation support, they have successfully completed the transition from pre-clinical studies to a Phase I and most recently a Phase II trial. The Phase I trials demonstrated the high safety profile of FAHF-2 and suppression of basophil activation and diminution of Th2 polarization of FAHF-2, reproducing

19

findings seen in the murine model. The initial Phase II trial was hampered by non-compliance due to the high daily pill intake required, but a new refining process has led to an 80% reduction in the daily dose requirement, and a new Phase II trial has just received funding. A number of active compounds comprising FAHF-2 have been isolated and identified, and their effects on immune functions elucidated. In addition, Dr. Li’s team has developed a novel herbal formulation, ASHMI, for the treatment of asthma. In Phase II clinical trials, ASHMI was shown to be an effective stand-alone asthma therapy for moderate to severe asthma when compared to prednisone, but with much less adverse side-effects. The combination of ASHMI and inhaled steroids was shown to be safer and more effective than steroid alone in children. Preclinical studies have demonstrated that ASHMI induces more long-lasting protection than corticosteroids in both eosinophil and neutrophil predominant models. Ongoing studies include the development of a new version of ASHMI by combining refined sub-fractions with more potent effects on bronchial smooth muscles, goblet cell secretions and immune function to increase pharmacological potency and ease of clinical use. Berin Lab The Berin Laboratory is focused on understanding the immune basis of allergy and tolerance to foods. Using murine models of food allergy, they have studied how interactions between intestinal epithelial cells, dendritic cells, and T cells contribute to sensitization to foods and to gastrointestinal manifestations of food allergy. Epithelial cells form the interface between the external environment and the mucosal immune system, and the Berin lab has made significant contributions to our

understanding of the contribution of epithelial cells to the pathogenesis of food allergy. They identified epithelial expression of CD23, the low-affinity IgE receptor, as a major mechanism for uptake of allergens from the gut lumen. They have also delineated the role of epithelial-derived cytokines and chemokines in the inflammatory response to food allergens in the intestine. Their work has also led to an understanding of how gastrointestinal dendritic cells orchestrate the development of allergic sensitization to foods. Current areas of focus include the use of these models to develop and refine novel immunotherapies for the treatment of food allergy, as well as to understand the basis of food allergenicity. In addition to mouse models of food allergy, the Berin Laboratory works closely with clinical collaborators in the Jaffe Food Allergy Institute in order to understand the immune basis of allergy and tolerance to foods. As part of the mechanistic core for the NIH-sponsored Consortium for Food Allergy Research, they have developed novel approaches to immunophenotyping the response to foods, including sensitive ex vivo detection of low-frequency allergen-specific T cells, CyTOF-based phenotyping, and transcriptional profiling of responses to allergen. By applying these approaches to subjects undergoing experimental allergen immunotherapy, the goal is to identify novel mechanisms and therapeutic targets to reestablish immune tolerance to foods.

• • •

Diagnosis •

• •

Epidemiology

20

Demonstrated the relationship between individual foodspecific serum IgE levels to clinically reactive food allergy and established diagnostic predictive values that are now used worldwide Identified important component proteins of food allergens for improving diagnostic accuracy Developed a peptide microarray that allows identification of allergenic epitopes in foods, which provide more specific information about clinical reactivity, severity and long-term outcome

Treatment •

Achievements Over the years, members of the Institute have achieved a number of major milestones:

Identification of risk factors for food-induced anaphylaxis, a severe and potentially fatal allergic reaction Demonstrated over a tripling of peanut allergy prevalence in the U.S. pediatric population since the late 1990’s Discovered that food allergy is the major cause of eosinophilic esophagitis (an inflammation of the esophagus) in most children

• •

Demonstrated that heat-denatured (baked) forms of milk or egg are tolerated by a majority with those allergies and that introduction of baked- milk/egg products into the diet of those milk/egg allergic children accelerates the development of full tolerance to all forms of these foods Conducted studies of novel therapies using ingredients from traditional Chinese medicine Developed a novel food allergy vaccine using engineered mutated peanut proteins

• • •

Conducted the first placebo-controlled study of egg oral immunotherapy Conducted the first placebo-controlled trial of dual therapy (immunotherapy and anti-IgE) Conducted the first placebo-controlled trial of anti-IgE (TNX-901 & omalizumab) for food allergy

Future Recently recruited faculty will expand the scope of investigation of food allergy in the Institute. Dr. Supinda Bunyavanich, MD, and others are studying how food allergic patients’ genetic predisposition is dynamically shaped by eating food during a food allergic response. Using blood from peanut allergic

21

patients undergoing oral peanut challenges, she is analyzing how the interpretation and transcription of their DNA is modified by food allergen exposure. In conjunction with Drs. Jose Clemente, PhD, and Jeramiah Faith, PhD, members of the Institute will evaluate the role of the gut microbiota in shaping the allergic and tolerogenic response to foods. Finally the Sampson and Berin labs will continue to investigate the immunologic effects of novel immunotherapies, including a nanoparticle-based peanut vaccine, algae-based engineered peanut protein vaccine and a T-cell peptide-based peanut vaccine in clinical trials, and attempt to identify biomarkers of tolerance induction.

Hugh A Sampson is the Kurt Hirschhorn Professor of Pediatrics, the Dean for Translational Biomedical Research, PI and Director of Conduits; Institutes for Translational Sciences, and the Director of the Jaffe Food Allergy Institute at the Icahn School of Medicine at Mount Sinai. Dr. Sampson completed his allergy/immunology fellowship training at Duke University in 1980 and was a faculty member in the Division of Allergy/Immunology at Duke University and then Johns Hopkins University before coming to Mount Sinai. He has published over 400 articles and 60 book chapters on food allergic disorders and co-edited four books, and was elected to membership in the Institute of Medicine of the National Academies in 2003 for his research in food allergies. Research Interests Mechanisms of Allergic Reactions to Foods. Dr. Sampson’s research focuses on food allergic disorders including the immunopathogenic role of food allergy in atopic dermatitis, eosinophilic esophagitis and anaphylaxis. His lab studies the role of food allergen epitope-specific IgE, histamine-releasing factors, and T cell responses in the clinical manifestations of these disorders and changes that are associated with the development of natural tolerance. Characterization of Food Allergens. In an attempt to better understand the difference between individuals with “sensitization,” i.e. presence of food-specific IgE antibodies, and

22

those with “symptomatic allergic reactions,” and to explain the small minority of foods in the diet that account for over 90% of food allergic reactions (milk, egg, peanut, tree nuts and seafood), the lab has focused on identifying and characterizing component proteins within foods that account for allergic reactivity. The lab has also focused on the epitope specificity of IgE binding to these allergenic proteins and is currently developing a high throughput assay that is more specific than conventional diagnostic tests and provides information regarding natural history and severity of potential allergic reactions. In addition, this work led to finding that ~80% of young children with milk and egg allergy can tolerate these foods in a heat-denatured (baked) form, which when introduced into the diet, accelerate the induction of natural tolerance, a practice that has now become the standard of care for children with milk and egg allergies. Immunotherapy for Induction of Desensitization/Tolerance to Food Allergens. Dr. Sampson is the PI of the NIH-sponsored Consortium on Food Allergy Research and an AADCRC program project conducting a number of clinical trials investigating novel therapies for the treatment of food allergy. These trials include the use of oral immunotherapy, sublingual immunotherapy, epicutaneous immunotherapy, and the use of a novel engineered recombinant peanut protein vaccine. Dr. Sampson and his team are currently developing a peptide-based vaccine and a CpG-nanoparticle-based vaccine for treating peanut allergy, the latter of which is under review for a phase I clinical trial.

M. Cecilia Berin received her PhD in Medical Sciences (Physiology & Pharmacology) from McMaster University in Hamilton, Canada. She completed postdoctoral training in mucosal immunology at the University of California, San Diego prior to joining the Icahn School of Medicine at Mount Sinai as faculty. She is currently an Associate Professor in the Department of Pediatrics, Division of Allergy and Immunology. Research Interests Mechanisms of allergic sensitization to foods The default immune response to antigen exposure through the gastrointestinal tract is active regulatory tolerance. Dr. Berin’s laboratory is interested in understanding how these mechanisms are subverted to result in the generation of Th2biased immunity and generation of allergen-specific IgE. Her work has focused on the communication between gastrointestinal epithelial cells, dendritic cells, and T cells in the generation of allergic sensitization. Current work is focusing on innate responses to food allergens and the regulation of sensitization through epicutaneous exposure. Pathophysiology of IgE-mediated and non-IgE-mediated reactions to foods In allergic individuals, oral exposure to food allergens can result in a diverse set of manifestations affecting the gastrointestinal tract, skin, and lung. Dr. Berin’s lab has studied the mucosal

23

response to food allergens underlying gastrointestinal manifestations of food allergy, primarily focusing on the central role of epithelial cells. Her lab has shown that IgE and the low affinity IgE receptor are involved in both the facilitated antigen uptake of allergen across the epithelium and the induction of chemokines from intestinal epithelial cells. Epithelial derived chemokines (CCL20) and cytokines (TSLP) direct the recruitment and amplification of pathogenic Th2 responses in the gut. Current projects include elucidating mechanisms of gastrointestinal manifestations of non-IgE-mediated food allergy, and defining the role of neuro-immune communication in gastrointestinal and systemic manifestations of food allergy. Immunotherapy for the induction of tolerance to foods The overall mission of the Berin lab is to identify immune mechanisms for the prevention and treatment of food allergy. One approach to understanding immune mechanisms of acquired tolerance to foods is by studying patients who have outgrown their food allergies, either through intervention (allergen immunotherapy) or by natural outgrowth. In association with natural history and intervention trials being conducted at the Jaffe Food Allergy Institute, the Berin lab in collaboration with the Human Immune Monitoring Center and the Flow Cytometry Core is using novel approaches to identify mechanisms and biomarkers of acquired tolerance to foods.

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Immunodeficiency

The

Primary Immunodeficiency Program at Mount Sinai,

established in 1986 by Dr Cunningham-Rundles is now a 950 out patient service, uniquely spanning medicine and pediatric departments. Due to the numbers of patients with rare immune defects, Mount Sinai has been a site for clinical investigation, trials of cytokines, monoclonal antibodies, biologics, commercial and investigational IV and SC immune globulins, and IgA-rich preparations for reinforcing mucosal immunity. This program is a unique resource for research, and has an established DNA, RNA, cell and serum bank. The Immunodeficiency Program provides a strong clinical interface for medical student teaching, T32 Training Program, and postdoctoral training and the MD/PhD program. It also provides a major attraction for applicants to the Allergy Immunology Fellowship, one of the largest and most competitive in the United States. Since 2003, the laboratory of Benjamin Chen has been investigating the viral exploitation of T cell biology and the acquired immunodeficiency mediated by human immunodeficiency virus infection. The laboratory has been recently relocated to newly designed space in the Annenberg 23 where a state-of-the-art system for immune cell imaging has been developed. Goals The overall goals are: 1) Elucidation of the mechanisms of genetic disease and 2) Dissection of the mechanisms of acquired immunodeficiency engendered by HIV infection. Team 25

The team of investigators in the Primary Immunodeficiency Program include a medical team and research investigators in the Immunology Institute including Drs. Cunningham-Rundles, Andrea Cerutti, Patricia Cortes, George Diaz, Sergio Lira, and Adrian Ting. Added to this team are colleagues at Rockefeller University: Drs Jean-Laurent Casanova, Bertrand Boisson, and Mary Ellen Conley, and at Yale, Dr Eric Meffre. Investigators dedicated to understanding the dysregulation of the immune system during HIV infection and the acquired immunodeficiency syndrome include Drs. Benjamin Chen, Nina Bhardwaj, and Judy Aberg. Themes Genetic Defects of B cells: One of the most puzzling immunodeficiency disease, is the heterogeneous B cell defect, common variable immune deficiency (CVID). With the very large cohort of subjects with CVID who seek care at MSSM, the laboratory has investigated many aspects of this immune defect, including cellular, molecular and epidemiologic studies. Current work focuses on the genetics of these defects. One example are TACI mutations which are found in homozygous and heterozygous states in patients and their family members and lead to defects of signaling, hyperproliferation, and in the escape of autoimmune clones. Using subjects with these defects, Dr Cunningham-Rundles in collaboration with Dr. Cerutti, showed that this unique receptor uses MYD88 as a requirement for signaling. In Smith Magenis syndrome, one TACI allele is deleted, leading to a model of haploinsufficiency used in other studies. Unlike mice, human TACI is produced in two isoforms; Dr Cunningham-Rundles in recent work with Dr Adrian Ting showed that the truncated isoform is the potent signaling receptor for plasma cell generation and predict that

these isoforms control this step of B cell maturation and provide a potential target for biological intervention. Aside from TACI, other gene mutations leading to congenital B cell defects are being sought in families with several affected members, and subjects with very early onset of immune dysfunction using whole genome sequencing, with interesting candidates being several novel X chromosome genes, also BCMA, and PI3 kinase delta 110, which are being intensively studied by the investigator team. TLR Induced Antibody responses: Patients with mutations in IRAK4 and or MYD88 have severe bacterial infections but IgG responses to carbohydrate antigens appear preserved. However, the loss of CD27 IgM+ memory B cells in these subjects, suggests loss of IgM glycan “natural” antibody. Recent work of Dr Cunningham-Rundles with Drs. Cerutti and Casanova, shows a generalized loss of serum glycan antibodies (Glycomics array: http://www.functionalglycomics.org), suggesting a basis for these infections. Normal human CD27 IgM+ B cells preferentially proliferate with TLR agonists, thus loss of TLR signals impair expansion and differentiation, and potentially protective, antibodies. In other work, using high throughput sequencing, the B cell CDR3 of TLR activated B cell subjects are being examined with investigator at Stanford, showing preferential V-region usage, with secretion of poly-reactive antibodies, distinctly different from other B cell activators. Loss of B cell tolerance: In humans the mechanisms that account for auto-reactive B cells and autoantibody production remain elusive. A central B cell tolerance checkpoint in the bone marrow removes the majority of developing B cells that express poly-reactive antibodies allowing a small fraction of clones with low levels of poly-reactivity to migrate to the periphery. In this 26

continuing project Dr Cunningham-Rundles, Drs. Meffre and Cerutti, are examining B cell tolerance checkpoints using discrete genetic defects on XLP, AID, TLR, and TACI. Inflammatory/Autoimmune Disease: In a cohort of 476 subjects with CVID, a hallmark was that about 50% of patients have, in addition to infections, a group of inflammatory/autoimmune complications, which in aggregate, lead to an 11-fold increase in mortality which is not altered by standard immune globulin replacement. This issue is now the main clinical concern but it presents an unsolved puzzle as to the pathogenesis. We demonstrated an interferon signature in these subjects using RNA microarray, and we are now investigating the origin of this signature using CyTOF. Preliminary studies by Drs Cunningham-Rundles, Lira and Blander, indicate an expansion of innate lymphoid cells in blood and affected tissues. T cell interactions and viral dissemination: In the past nine years it has become increasingly clear that the human immunodeficiency virus exploits the capacity of T cells to communicate with other immune cells to facilitate viral dissemination. Research in the Chen laboratory has used advanced light and electron microscopy imaging approaches study the dynamics of virological synapse formation. These are virus-induced adhesions that communicate viral infection between immune cells. These structures share many features with immunological synapses, the fundamental unit of immune recognition, but are triggered by unique viral mechanisms and appear to facilitate immune evasion. The laboratory has specialized in developing genetic tools to elucidate the cell biology of virological synapse-mediated transmission.

Small animal models of the human Immune system: The study of human immune defects and infectious agents that only infect the human immune system has been greatly advanced by the development of highly immunodeficient mice that can be exploited as hosts for xenografted human immune stem cells. We have been developing virological tools and imaging methods that now allow us to study the behavior of HIV infected human T cells within 3-dimensional lymphoid tissue settings that do not require artificial exogenous cytokine or receptor stimulation to activate viral infection. We are developing methods to image infected immune cells within the spleen, gastrointestinal tract, and lymph nodes in humanized mice using a dedicated biohazard-contained two-photon microscopy suite in our laboratory. Achievements From the original cohort of patients brought to Mount Sinai from Sloan Kettering by Dr. Cunningham-Rundles the current service has grown steadily each year, now numbering 800 - 900 patients from the NYC, surrounding and other states. The program spans medicine and pediatrics at Mount Sinai. As of 2010 it is the largest referral site for infants with abnormally low TRECs, indicating severe T cell dysfunction such as SCID. The patient group has been a major resource for the development of grant funding, which includes a Program Project on B cell defect, now in its 11th year, as well as an R18 Demonstration and Education grant now in it 12th year, based on a computer algorithm we invented to identity undiagnosed patients with immune deficiency in electronic medical records, using disease coding. Overtime clinical trials for most of the currently licensed immune globulin products have been tests in this program, and cytokines such as gamma-interferon and IL-2, have been used in 27

various studies. In the past five years alone, research and clinical studies of the patient group has been the basis for 51 peer reviewed articles. While one of the main focuses of this program has been the B cell defects, patients with may other immune defects receive care, chronic granulomatous disease, X linked agammaglobulinemia, hyper IgE, Wiskott Aldrich syndrome, Hyper IgM Syndrome, severe combined immune deficiency, DiGeorge syndrome, as well as very rare disorders such as DOCK8, GATA2, LAD2, cartilage hair hypoplasia, XLP and NEMO defects. Another important achievements were the routine development of highly immunodeficient mice that can be exploited as hosts for xenografted human immune stem cells and the establishment of a dedicated biohazard-contained two-photon microscopy suite. Future Research in the Primary Immunodeficiency Program: With the expanding number of genetic diseases defects, we are in the midst of seeking defects that lead to impaired B cell function, using whole-genome sequencing and with the application of novel tools, new candidates are now emerging. These will lead to new insights into normal B cell function as well as opportunities for therapeutic advances. Currently a group of mutations in PI3 kinase 110 delta, now found in 50+ subjects, is attracting interest, as these are additional inflammatory complications potentially susceptible to treatment with a novel PI3 kinase110 delta inhibitor. Research in the Viral Immunodeficiency Program: We are developing new methods to correlate live light imaging

approaches with ultrastructure to better characterize the cellular structures that underlie viral transmission. We are also working to develop reverse genetic methods in our humanized mouse models to probe specific genetic pathways that support the spread of HIV through T cells. These methods will be generally applicable to create humanized models of immunity/immunodeficiency or to test gene repair approaches in stem cells from genetically deficient individuals. Clinical program: We expect further expansion of the program at Mount Sinai and the opening of a new center at one of our new sites. As subjects with primary immunodeficiency have an alarming incidence of inflammatory and autoimmune disease, more targeted immune therapies will be needed for this patients, and will be tested at this site.

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Charlotte Cunningham-Rundles received her bachelor’s degree from Duke University, MD from Columbia College of Physicians and Surgeons and PhD from New York University. Her internal medicine training was in at New York University Bellevue Hospital, after which she went to Memorial Sloan Kettering Cancer Center as an Associate Member and Director of the Biochemical Immunology and Immunodeficiency Laboratory. At Mount Sinai, she is a Professor of Medicine and Pediatrics and the David S. Gottesman Professor of Immunology, Program Director of the Allergy Immunology Fellowship, and acting Chief of Clinical Immunology. Dr. Cunningham-Rundles has served as Chair of NIH Allergy Immunology and Transplantation Committee, the Immunology Review Committee of NASA and served on the FDA Blood Safety and Advisory Committee, and the Medical Advisory Boards of the Immune Deficiency Foundation and the Jeffrey Modell Foundation. She is a member of the Henry Kunkel and the Harvey Societies. She is a past President of the Clinical Immunology Society and member of the Board of the American Academy of Asthma Allergy and Immunology. She is a member of the Expert Committee on Immune Deficiency, IUIS, and founder and Principal Investigator of the USIDNET, a research consortium funded by the NIH. Research Interests We investigate primary defects of human B cells, the causes, treatments and outcomes. While few of the immune defects leading to loss of B cell development known, the genetic reasons for loss of this key adaptive function remain to be elucidated. 8% of subjects with common variable immune 29

deficiency (CVID) have mutations in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a still enigmatic receptor which activates and yet regulates B cell function. We have used naturally occurring mutations in TACI to investigate signaling pathways, regulation of isotype switch, and control of tolerance in human B cells. Current studies show that differential use of TACI isoforms provides essential but unanticipated regulatory controls on plasma cell development. On whole exome sequencing, LRBA and PI3Kd gain-of-function mutations have emerged as causes of complex B cell defects with immune dysregulation and risk of lymphoma, which allow novel opportunities to understand inflammatory networks in CVID and to use targeted treatment strategies. T and B cell receptors High-through-put sequence analysis of the CVID IgH repertoire has revealed novel disease mechanisms and phenotypic features, including aberrant gene rearrangement in the bone marrow, decreased V gene replacement, decreased naïve B cell repertoire diversity, impaired somatic hypermutation, and abnormal expansion of unmutated B cell clones. Suggesting unifying stem cell defects, TCR β CDR3 TCR analyses also show increased germline sequences, and greater clonality, unrelated to age, sex, or clinical complications. Cohort studies The very large referral base for pediatric and adult patients has led to an unparalleled patient population with genetic immune disease. This has enabled large scale studies of the natural history, outcomes, and optimal treatments of these rare defects and continual opportunities for extensive collaborative research.

Benjamin Chen received his MD from Weill Medical College of Cornell University and PhD from Rockefeller University in New York. He conducted his postdoctoral training in the Department of Biology at the Whitehead Institute for Biomedical Science at Massachusetts Institute of Technology in Cambridge, MA. He is currently an Associate Professor of Medicine/Infectious Diseases at the Icahn School of Medicine at Mount Sinai in New York. He is a recipient of the NIH/NIDA Avant Garde Award for innovative HIV research and is a Burroughs Wellcome fund Investigator in the Pathogenesis of Infectious Disease. He is actively involved with the MD-PhD program as an assistant director and is graduate mentor associated with the Immunology and Microbiology graduate training areas. His research has explored the interface between immune cell biology and virology that allows HIV-1 to maintain a persistent infection. Research Interests Mechanisms of HIV-1 virological synapse formation Dr. Chen’s lab is interested in HIV-2 virological synapses, infectious structures formed between human immunodeficiency virus-infected T cells and uninfected CD4+ T cells called virological synapses. Live confocal imaging studies from his laboratory studying fluorescent viral clones revealed a dynamic ordered process of cell-cell adhesion and the active recruitment of viral proteins at these structures. His group has also helped to 30

characterize how the viral membrane fusion process is controlled during infection through virological synapses. Immune evasion through infection by T cell virological synapses Dr. Chen’s lab also discovered that neutralization of HIV-1 infection by patient antibodies is more difficult when the infected cells are mixed with target cells, as compared to infection through cell-free virus particles. The relative resistance to neutralization could be observed with both patient sera as well as with monoclonal antibodies. The laboratory was the first to indicate that the resistance is likely to be due to conformational masking mechanism that is coordinated with cell-to-cell transmission of HIV. Parenteral Transmission of HIV and the movement of infected cells in humanized mice Using humanized mouse models, the Chen lab has been studying the efficiency with which cell-free and cell-associated HIV-1 becomes established in lymphoid tissues during parenteral HIV transmission. Ongoing studies are testing whether the spread of virus within lymphoid tissues is through occurs in spatially restricted clusters or through a diffuse cloud of plasma virions. Intravital imaging studies have been characterizing the movement of infected T cells in humanized mice and explanted lymphoid tissues.

Human Immune Monitoring Center 31

The

Human

Immune

Monitoring

Center

(HIMC)

was

established three years ago within the Tisch Cancer Institute at Mount Sinai as a core service to support cancer trials. It has since grown into a shared resource available to the Immunology Institute members and to members of the Icahn School of Medicine at Mount Sinai. Goals 1. To provide a comprehensive assessment of the immune status in patients. 2. To discover immune profiles of disease, leading to new biomarkers of diagnosis, prognosis, and response to therapy. 3. To quantitate immune responses and help optimize drug dose, delivery, schedule, and combinations. 4. To identify immunomodulatory effects of novel drugs in clinical trials. 5. To develop and implement novel technology that will expand and strengthen our ability to probe immune cell function in humans. Team Drs. Merad and Gnjatic co-direct the Immune Monitoring Center. Dr. Gnjatic is an expert in defining antibody, and CD8+ and CD4+ T cell responses to tumor associated antigens using state-of-the-art technologies, and has considerable experience implementing these approaches for quantitative and qualitative assessment of immunotherapy trials. Dr. Merad is an expert in myeloid cell biology whose work established many phenotypic and functional roles of monocytes, macrophages, and dendritic cells in the periphery and in the tissue microenvironment. The

32

team also includes a Facility Director, Dr. Seunghee KimSchulze, a Clinical Research Coordinator, a Regulatory Affairs Specialist, and four Research Technicians. Services and Platforms The HIMC team helps define optimal project-specific immunologic assessment and implements innovative approaches with a high degree of quality control and reliability. Together with the investigator, the HIMC defines the endpoints and parameters of immune assays, sample and processing requirements (collection, labeling, storage, handling, and shipping), reagents and controls, data analysis, data management expectations and estimated costs. The research environment includes several small adjacent lab spaces, a flow cytometer, laminar hoods, freezers and liquid nitrogen storage, and automated instrument platforms for ELISA and RNA isolation, with all methods and procedures handled by validated SOPs. The HIMC team also assists with grant writing by providing templates for immunological correlates, budget details, and letters of support to accompany the grant application. State-of-the-Art Assays The HIMC offers state-of-the-art immune assays including: 1. Detailed immunophenotyping of lymphoid and myeloid immune cell subsets circulating in the blood or residing in tissues by flow and mass cytometry and immunohistochemical analyses, 2. Detailed analysis of humoral immune responses from plasma or serum using Multiplex, ELISA and seromics,

3. Antigen-specific T cell assays ex vivo or after in vitro sensitization using ELISPOT, intracellular staining of cytokines, CD154-selection, CFSE-based proliferation assays for Treg function, and cytokine detection via Multiplex assay. 4. Semi-automatic nucleic acid isolation from purified cell populations isolated from the blood or tissues, 5. Genome and transcriptome profiling using next generation sequencing of purified immune cell populations in collaboration with the Genomic Core at Mount Sinai. In addition, we would like to highlight the acquisition and implementation of two novel platforms: Mass Cytometry: CyTOF Mass Cytometer (DVS Sciences) is a multiparametric biological analyzer, similar to flow cytometry except that it operates based on time-of-flight mass cytometry. Using antibodies tagged with various heavy metal ions, over 80 parameters can be analyzed simultaneously in a single tube at a high acquisition rate without the need for compensation. We have supported the acquisition of a Mass Cytometer by the School, and are developing and standardizing comprehensive immunophenotyping panels for CyTOF in collaboration with the Flow Cytometry Research Facility. Seromics: Seromics is an exploratory, hypothesis-generating platform that allows the testing of thousands of human proteins simultaneously as potential targets of autoantibodies from patient serum or plasma. The method only requires a few microliters of material, and may be customized for applications other than IgG antibody detection. It is ideally suited to comprehensively look for serum antibody changes at the antigen-specific level following interventions such as immunotherapy, vaccine, chemotherapy, or radiotherapy.

33

Alternatively, the seromic platform can be used to define biomarkers or sets of antigens present at baseline in specific patient populations, which in turn could be used as prognostic or predictive markers. Achievements The HIMC is currently engaged in 21 active clinical trials or studies and has contributed to the immunomonitoring plan of a number of grant applications, of which 18 have already been funded for a total of nearly $16 million, generating substantial indirect costs for the Icahn School of Medicine. The HIMC supports studies in cancer (tumor immune responses, immune monitoring of antitumor therapies), cardiovascular disease (gene therapy trial, role of monocytes in cardiac disease), food allergy (mechanisms of disease), genetics (disease pathogenesis), IBD (mechanism of disease), infectious disease (influenza-induced immune response), ophthalmology (biomarkers of dry eye disease), pediatrics (vaccine-induced immune reactions), and psychiatry (immune targets of depression). We currently have several contracts with pharmaceutical and biotech companies. These include Pfizer (immunomodulation of new drug), Imclone (new target of disease), Dendreon (immunomodulation of new drug), Genentech (immunomodulation of new drug), Immune Design (cancer vaccines), Advaxis (cancer vaccines), Janssen R&D (biomarker study). We expect the number of such interactions to grow, allowing for additional budgetary income from our operations. In addition, we are partnering with industry for implementation of novel technologies such as TCR sequencing (Adaptive Biotech), which will be offered as part of our roster of assays.

Future Our near future goal is to remain at the forefront of technology development by introducing novel assays, methods, and instruments that expand the scope of immune analyses. Such investment is crucial for providing the best means to dissect immune dysregulation in patients and to discover new disease targets. There is accumulating evidence that immune responses are compartmentalized and that circulating cells do not always capture the immune events that occur at the tissue site. Yet most technology efforts have focused on immune analysis of circulating blood cells and many assays are not adapted to characterize tissue immune infiltrates. We plan to build a tissue immune contexture platform for “in situ Immunology” that will help assess the nature, dynamics and molecular characterization of the immune cells that infiltrate human tissues. This platform will be centered on:

Sacha Gnjatic received his PhD in Immunology from the University of Paris VII in France. He conducted his postdoctoral training at the Ludwig Institute for Cancer Research at Memorial Sloan-Kettering Cancer Center in New York, NY, where he went on to eventually become an Associate Member. He is currently an Associate Professor of Medicine / Hematology Oncology at the Icahn School of Medicine at Mount Sinai in New York. He is also the Associate Director of the Human Immune Monitoring Center at Mount Sinai. He is a member of the Scientific Advisory Board of several cancer vaccine and immunotherapy programs (Broad Institute, NCI CITN, Boehringer-Ingelheim, Janssen R&D), as well as an Adjunct Associate Professor at Roswell Park Cancer Institute in Buffalo, NY. Dr. Gnjatic also serves on the editorial boards of Cancer Immunity, Cancer Immunology Research, and Frontiers in Immunology. Research Interests The search for specificity: Antibody and T cell responses to tumor antigens Dr. Gnjatic’s lab specializes in the characterization of serological and cellular immune responses against tumor antigens such as NY-ESO-1, p53, MAGE-A3, for their capacity to induce immune responses both spontaneously and in the setting of cancer immunotherapy. Dr. Gnjatic also pioneered large-scale seromic profiling using high-density protein arrays to find biomarkers and new targets of tumor immunity.

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Profiling immune responses in cancer immunotherapy As part of the Cancer Vaccine collaborative and in collobaration with industry, Dr. Gnjatic and his laboratory have participated in the immune monitoring of more than 1800 patients across 50 tumor immunotherapy clinical trials, including cancer vaccines and checkpoint blockade inhibitors. Recently, Dr. Gnjatic designed and analyzed results from a human vaccine based on NY-ESO-1 long overlapping peptides that showed the highest immunogenicity compared to all NY-ESO-1-based vaccines tested to date, and demonstrated the respective role and importance of immunological adjuvants poly-ICLC and montanide. Regulation of immune responses and immunotherapy Beyond the definition of immune responses to cancer, Dr. Gnjatic’s lab also asks how therapies work and why they may fail. Areas of research include 1) Mechanisms of antigen presentation to T cells, such as defining epitopes, evaluating viral, bacterial, and parasitic vectors, cross-presentation of antigen to HLA class I, and endogenous antigen presentation to HLA class II; 2) Impact of immunoregulation on tumor antigen-specific responses, from co-inhibitory molecules expressed on T cells at the tumor site to the effect of regulatory T cells on anti-tumor effectors; and recently 3) Importance of the microenvironment and immune contexture in the tumor, with implementation of immunoscore analyses and correlations with markers of suppression and presence of tumor antigens.

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Immunotherapy

The

Immunotherapy program encompasses an integrated

multidisciplinary effort with primary focus in the areas of food allergy, immune deficiency, immune based disease, and cancer. The Jaffe Food Allergy Institute, founded in 1997, researches the mechanisms underlying food allergy and develops immunotherapeutic approaches to induce tolerance to allergic reactions against milk, egg, peanut and wheat. The Immunodeficiency Clinic at Mount Sinai, treats patients with primary immunodeficiency diseases and common variable immunodeficiency (CVID) and oversees the design of therapies to restore immune dysfunction in these conditions. The Cancer Immunotherapy program, was formally established in 2013 under the auspices of the Tisch Cancer Institute. Goals 1) Translate innovative preclinical models into high impact clinical trials. 2) Develop novel vaccines and cell-based immune therapies for the treatment of cancer, infectious diseases and autoimmune diseases. 3) Provide a dedicated, controlled space to manufacture human therapeutics for Phase I and II clinical trials in accordance with current Good Manufacturing Practice (cGMP) as required by the FDA. 4) Provide a dedicated space for treatment and clinical research Team Dr. Nina Bhardwaj has made seminal contributions to human dendritic cell biology, specifically with respect to their isolation,

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biology, antigen presenting function, and use as vaccine adjuvants in humans. Together with Dr. Merad, Dr. Bhardwaj co-leads the Cancer Immunology Program, which interfaces closely with Immunology Institute. She is the Director of Immunotherapy and also heads the Cancer Immunology Steering Committee of the AACR. She has overseen more than a dozen investigator initiated immunotherapy trials and is also Medical Director of the Vaccine and Cell therapy Facility. Drs. Rachel Sabado and Marcia Mesek are the Vaccine and Cell Therapy Facility Director and QA/QC managers, respectively. Dr. Sabado has had oversight of >30 studies and was involved in the preparation of over 600 individual vaccines for patients with melanoma, glioblastoma, breast cancer, ovarian cancer and pediatric tumors. Marcia Meseck, PhD, Assistant Professor, Dermatology is the QA manager for the Vaccine and cell Therapy facility and the Human Immune Monitoring Core (HIMC) and brings >20 years of experience to the facility. Dr. Hugh Sampson oversees the Jaffe Food allergy Institute, which comprises over 60 members and sees more than 6000 patients per year. Dr. Sampson’s research interests focus on food allergic disorders, the pathogenesis of food-induced anaphylaxis, characterization of allergenic food proteins and their processing by the immune system, genetics of food allergy, and development of mechanisms of immunotherapeutic strategies for treating food allergies including the potential use of biologics, such as anti-IgE and anti-cytokine monoclonal antibodies. Dr. Charlotte Cunningham Rundles is the Director of the Immunodeficiency Clinic, which sees pediatric and adult patients with many forms of known or suspected immunodeficiency, and investigates primary defects of human B

cells, the causes, treatments and outcomes. She oversees a large referral base for patients, that have enabled large scale studies of the natural history, outcomes, and optimal treatments of these rare defects. She is the Director of the Therapeutic Infusion Center for biologic therapy for immunebased diseases. Dr. Miriam Merad and Sacha Gnjatic co-direct the human Immune Montioring Center. Dr. Gnjatic is an expert in defining and developing approaches to assess antibody, CD8+ and CD4+ T cell responses to tumor associated antigens. Dr. Merad is a pioneer in the evaluation of myeloid lineage subsets including monocytes, macrophages and dendritic cells. Dr. Thomas Moran is the Director of the Center for Therapeutic Antibody Development (CTAD). He oversees the technology to produce human monoclonal antibodies using both mouse models and human cells. Resources The Vaccine and Cell Therapy Facility, the Human Immune monitoring Core (HIMC), the Center for Therapeutic Antibody Development (CTAD), and the Therapeutic Infusion Center provide the necessary infrastructure to meet the multidisciplinary needs of Immunology Institute (II) members. The Vaccine and Cell Therapy Facility is a dedicated facility for the manufacture of immune therapies. It has the capacity to prepare vaccines and cellular immunotherapies in a dedicated, controlled space in accordance with current Good Manufacturing Practice (cGMP) regulations as required by the

38

US Food and Drug Administration (FDA). This cGMP laboratory features four class 10,000 (ISO 7) cleanrooms, with a Panasonic isolator, biosafety cabinets, cell counters, microscopes, Clinimacs cell separator, incubators, liquid nitrogen storage and controlled rate freezers. It has been designed with the flexibility to manufacture virtually any type of therapy that uses manipulated human cells. The Center for Therapeutic Antibody Development (CTAD) is a state of the art facility for the production of monoclonal antibodies. The facility is completely automated with Hamilton/Stem Cell clone picking robot (ClonaCell EasyPick STAR Robotic System), automated ELISA washing and reading, Octet analyzer for marker free analysis of binding and affinity measurements Intellicyt high throughput 5 color flow cytometer, Luminex multiplex ELISA analyzer and a state of the art electroporation unit for animal DNA immunization. The staff is 7 persons in addition to Dr. Moran, two assistant professors and 5 research associates with advanced degrees. Dr. Aneel Aggarwal, an internationally recognized crystallographer advises on protein production and purification. Therapeutic Infusion Center. Mount Sinai treats a number of patients who need regular infusions of immune globulin for immunodeficiency, autoimmunity, or neurologic disease. The growing number of monoclonal antibody therapies available for inflammatory bowel disease, rheumatoid arthritis, lupus, polymyocytis, gout, post renal transplant, and the autoimmune blistering diseases, provided the impetus to expand our activities. The Therapeutic Infusion service was consolidated and moved to a new larger space in the Hess Building in April 2013. This resource is directed by Dr. Cunningham-Rundles with its own staff, and a dedicated pharmacy. This space is also used for

investigational studies such as mepolizumab for eosinophilic syndromes and polyclonal anti RSV immune globulin in a safety study. Achievements 1. Cancer immunotherapy. Drs Bhardwaj, Brody, Gnjatic, Merad, and Sikora apply combinations of unique immune modulators, novel vaccines, adoptive cell therapies and checkpoint blockade inhibitors to treat cancers. The Cancer Immunology program brings in revenues of more than 10 million dollars for a total of 61 projects that encompass preclinical and clinical research. Selected examples of ongoing clinical trials are listed in Appendix IV. Immune modulators: TLR agonists, also referred to as pathogen associated molecular patterns (PAMPs) are potent activators of DC and lead to the induction of strong antigen-specific T cell responses in vivo. II program members have: • Iteratively tested TLR agonists and identified CpG and polyICLC as the most potent adjuvants for the induction of tumor-specific immunity • Developed a novel vaccine strategy comprising whole irradiated tumor cells co-delivered with TLR agonists as an effective immunogen • Adapted this technology to create GMP grade cell-based vaccines in the Vaccine and Cell Therapy Facility for application to solid tumors • Developed a successful clinically active in situ “autovaccination” approach that combines low dose radiation and injection of a TLR agonist directly into the same tumor site to activate tumor infiltrating DC and promote tumor specific T cell immunity • Combined in situ auto-vaccination with intratumoral “Flt3L” 39

•

which recruits and promotes the survival of intratumoral DC to improve the in situ vaccine approach Demonstrated feasibility and efficacy of intratumoral therapeutic vaccination with Poly-ICLC of advanced multiple solid tumors

Vaccines: II members are testing novel vaccine formulations in the clinic, including unique antigen formulations, dendritic cell based vaccines and antigen-expressing bacterial vectors. Their achievements include: • Application of promising antigen formulations (long peptide formulations, viral vectors) to induce strong integrated immune responses in patients with ovarian cancer and melanoma • Development of potent dendritic cell vaccines that induce strong immune responses in vivo • Determination that DC vaccines actually function as vehicles for antigen rather than directly priming T cell immunity and are cross-presented by endogenous DC • Use of systemic immune modulators to improve crosspresentation of DC vaccines by endogenous DC • Testing cytokines such as IL-7 in combination with DC based vaccines (Provenge) in prostate cancer to improve immunity • Mobilizing and targeting DC in situ with Flt3-L and antigenDEC-205 antibody conjugates • Testing attenuated Listeria vectors bioengineered to secrete HPV16 E7 protein in Head and Neck cancers in the neoadjuvant setting Checkpoint blockade inhibitors: Monoclonal antibodies that reverse immune exhaustion (eg anti-CTLA-4, anti-PD-1 and antiPDL-1) have shown dramatic tumor regression in solid tumors. II members are combining these agents with other modalities to

improve their efficacy. They have: •

• • •

•

Demonstrated that the combination of anti-CTLA-4 (Ipilimumab) and cytoxan (to reduce T regulatory cells) in metastatic melanoma unexpectedly aggravates autoimmune side-effects. This significant observation urges re-examination of the effects of cytoxan on T regulatory function in vivo Conducted studies to test the combination of anti-CTLA-4 with Provenge vaccine in prostate cancer Conducted studies to test anti-CTLA-4 or anti-PD-1 in combination with HSV oncolytic virus (T-vec) Planned participation in a first of its kind multicenter, phase I, open label study combining ipilimumab with three different formulations of poly IC:LC/NY-ESO-1/Montanide vaccines Planned participation in a multicenter, CVC-sponsored Phase 1 study of a MEDI4736 (anti-PDL-1) and tremelimumab combination, in 6 disease-specific cohorts. This exciting combination is expected to synergistically impact tumor growth

Adoptive cell therapies (ACT). ACT approaches are proving to have great impact in T and B cell malignancies. Immunology Institute members are exploring these approaches in hematological malignancies. They have: • Identified two cancer-associated genes that are commonly expressed in myeloma cells, and associated with progression of disease and proliferation (the type I Melanoma Antigen GEnes (MAGE) CT7 (MAGE-C1) and MAGE-A3) • Shown that vaccination with MAGEA3 and TLR agonists efficiently primes humoral and adaptive immunity in patients pre-transplant • Determined that adoptive transfer of tumor antigen primed PBMC post-transplant maintains immunity 40

2. Immunotherapy for Food Allergy. Drs Sampson, Berin and Li have used a variety of immunotherapeutic approaches to treat food allergies. As examples, they have: • Demonstrated that heat-denatured (baked) forms of milk or egg are tolerated by a majority with those allergies and that introduction of baked- milk/egg products into the diet of those milk/egg allergic children accelerates the development of full tolerance to all forms of these foods • Conducted studies of novel therapies using ingredients from traditional Chinese medicine • Developed a novel food allergy vaccine using engineered mutated peanut proteins • Conducted the first placebo-controlled study of egg oral immunotherapy • Conducted the first placebo-controlled trial of dual therapy (immunotherapy and anti-IgE) • Conducted the first placebo-controlled trial of anti-IgE (TNX-901 & omalizumab) for food allergy that heatdenatured (baked) forms of milk or egg are tolerated by a majority with those allergies and that introduction of bakedmilk/egg products into the diet of those milk/egg allergic children accelerates the development of full tolerance to all forms of these foods • Conducted studies of novel therapies using ingredients from traditional Chinese medicine and also developed a novel food allergy vaccine using engineered mutated peanut proteins. • Conducted the first placebo-controlled study of egg oral immunotherapy, of dual therapy (immunotherapy and antiIgE) and of of anti-IgE (TNX-901 & omalizumab) for food allergy. 3. Monoclonal

Antibody

Development.

The

Center

for

Therapeutic Antibody Development (CTAD) provides program members with the capability to produce antibodies against unique immunological targets. The CTAD is invested in bringing monoclonal antibodies that have potential to impact cancer and autoimmunity into the clinic. The CTAD has: • • • • •

Produced monoclonal antibodies for the community for over 15 years Submitted two invention disclosures describing new technology for mAb production Licensed 15 new antibodies to commercial entities Generated more than 3 million dollars in antibody earnings over the last 10 years Formed partnerships and collaborations with USDA-Plum Island, Columbia University, Mass General Hospital, Vaxinnate Corporation, and MRC-Tech, London in addition to internal collaborations

derived hematopoietic progenitor cells Programmatic Development • Increase investigator initiated studies • Identify molecular, epigenetic and immune cellular signatures in the TME that provide predictive and prognostic data for immunotherapy • Interface with national organizations to bring new interventions to ISMMS • Develop and strengthen interactions of the Immunology Institute with the Experimental Therapeutics Institute now led by Dr. Paul Kenny.

Nina Bhardwaj received her undergraduate training from Wellesley College and completed her M.S., M.D., and Ph.D. training at New York University School of Medicine. Following an internship and residency in Internal Medicine at Brigham & Women’s Hospital, she trained at the Hospital for Special Surgery (Rheumatology) and The Rockefeller University (Immunology). Dr. Bhardwaj is currently a Professor of Medicine and Director of Immunotherapy at the Icahn School of Medicine at Mount Sinai. Research Interests Antigen presentation Dr. Bhardwaj’s Lab studies mechanisms by which human DCs acquire and process antigens derived from apoptotic cells. Her team has identified receptors utilized by DCs to phagocytose apoptotic cells, which either modulate DC immunity through the production of immunoevasive c y t o k i n e s , and others that promote immunity. Dr. Bhardwaj’s lab recently identified a new receptor for apoptotic cells, CD44, that imparts an inhibitory signal to DCs and which is being investigated as a tolerogenic target in vivo. The mechanistic basis of interaction between human DCs and viruses Although DCs exhibit high sensitivity in detecting pathogens; the fact that DCs are present in extremely low numbers in

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the body has made it difficult to understand their biology in HIV infection. Dr. Bhardwaj’s lab recently demonstrated that HIV activates DCs through TLR7. High-throughput microarray analysis is being used to gain insights into the global genomic changes that occur in DC subsets in response to HIV. In particular, the team is focusing upon TLR, RIG-I and infllammasome pathways to understand how HIV may affect DC function. Pathogenesis of human disease Dr. Bhardwaj’s lab focuses on subjects with melanoma and other cancers. They undertake genomic approaches to investigate the consequences of chronic inflammation and to identify pathways that drive oncogenic progression. Dr. Bhardwaj’s lab has also used state of the art immune monitoring and genetic approaches to analyze the changes in the immune response to infection and to metastatic disease. Immunotherapy Dr. Bhardwaj’s lab has undertaken several trials in melanoma and other cancers that are based upon potentiating the immune activating potential of dendritic cells. These have resulted in the generation of significant immune responses, w h i c h in some cases correlated with clinical outcome. This program has been expanded to subjects with brain, breast, p r o s t a t e , pancreatic and ovarian cancer. Additional vaccine platforms include adjuvants that target DCs in vivo as well, including TLR agonists and bacteria or virus based vector approaches.

Thomas Moran received his PhD from Boston University working with Drs. Vinay Kumar and Michael Bennett studying immunological response to organ transplant in small and large animal models followed by postdoctoral training in the laboratory of Dr. Hans Wigzell at the University of Uppsala, Sweden before returning to the US and the Department of Microbiology at Mount Sinai School of Medicine. Dr. Moran has published widely on immunity to virus infection using both mouse models and studies in human subjects. He served as the overall director of the NIH funded Center for Investigating Viral Immunity and Antagonism (CIVIA) that focused on studies of human immunology and infectious disease by advancing technological methodologies, supporting inventive research, serving as a conduit for collaboration and promoting exchange of scientific information. Among other projects CIVIA profiled the immune response of patients receiving the live-attenuated influenza virus vaccination (JID 2013). Dr. Moran served as the PI for the Viral Immunity in Pregnancy study (VIP) that analyzed changes that occur in women during pregnancy with an emphasis on understanding the enhanced susceptible to infection (JCI 2012). Currently in addition to his research interests Dr. Moran is the Director of the Center for Therapeutic Antibody Development (CTAD) here at Mount Sinai School of Medicine.

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Research Interests Program for Research Experimentation (PRIME)

on

Immune

Modeling

and

The project encompasses several research centers working in collaboration. In the interdisciplinary center at Mount Sinai School of Medicine PRIME has been actively mapping the regulatory network in viral infected dendritic cells by analyzing experimental data. Using this network, models and simulations have been developed to further our understanding of the innate immune response (J. Virology 2012). Innate immune factors influencing bacterial coinfection in influenza virus infected subjects The Moran laboratory is currently studying the role of innate cytokines released in response to influenza virus on the growth of coinfected Streptococcus pneumonia. Evidence suggests that the interaction between type 1 interferon and IL17 may be a crucial relationship that influences outcome (J. Virology 2012) Center for Therapeutic Antibody Development (CTAD) A number of collaborative projects are in progress aimed to develop monoclonal antibodies with therapeutic applications. Technology has been developed and is currently being used by CTAD to produce human monoclonal antibodies using both mouse models and human cells. Collaborations are ongoing with many of the Immunology Institute members (PNAS 2012).

Joshua Brody received his MD from SUNY Stony Brook School of Medicine and subsequently trained in Internal Medicine at Yale New Haven Hospital. He conducted post-doctoral training in the lab of Ed Engleman at Stanford University followed by a clinical fellowship in medical oncology and additional post-doctoral research in the lab of Ronald Levy. He is currently an Assistant Professor of Medicine in the Division of Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai in New York and Director of the Lymphoma Immunotherapy Program.

tumor-antigen-loaded DC for presentation to anti-tumor T cells. Pre-clinical modeling has demonstrated the efficacy of the approach and a phase I/II clinical trial was initiated in 2014. The first patients have completed therapy and demonstrated recruitment of BDCA1 and BDCA3 subsets to the tumor, activation of DC and T cell subsets, as well as tumor regressions at untreated tumor sites including lymph node, bone marrow and peripheral blood and appears to spare normal B cells while eliminating malignant B cells. Additional pre-clinical mechanistic studies are in progress while patient recruitment is ongoing.

Research Interests

Dr. Brody’s prior work assessed the ability of anti-tumor T cells to be selectively amplified and activated by transfer to the lymphodepleted host. Pre-clinical modeling demonstrated that such an ‘immunotransplant’ maneuver yielded greater antitumor efficacy compared to vaccination alone. A phase I/II clinical trial for patients with higher grade (mantle cell) lymphoma confirmed that the maneuver amplified tumorreactive T cell responses in comparison to vaccination alone. The Brody Lab has now shifted the focus to priming anti-tumor immune responses using checkpoint blockade antibodies (e.g. anti-CTLA-4 and anti-PD-1) and shown that immunotransplant can increase the anti-tumor effect of these therapies. Mechanistic pre-clinical studies have shown that transfer to the lymphodepleted host has potent effects on the signal transduction of activated T cells and their modulation by checkpoint blockade. An early phase clinical trial is being developed for patients with melanoma, multiple myeloma and aggressive lymphoma.

Flt3L-primed In Situ Vaccination for Lymphoma in Mouse and Man Dr. Brody’s lab has developed a novel therapeutic vaccine based on prior work while at Stanford initially using intratumoral administration of a TLR9 agonist to convert malignant B cells into ‘amateur’ antigen presenting cells. That work progressed from pre-clinical modeling to a series of clinical trials for patients with low-grade lymphoma showing that the approach could induce anti-tumor T cells and clinical remissions, some lasting for years. The new approach seeks to induce more powerful anti-tumor T cell responses by utilizing ‘professional’ antigen presenting cells, i.e, dendritic cells (DC) by combining: 1) intratumoral administration of Flt3L to recruit DC, 2) lowdose radiotherapy to release/load tumor antigens, and 3) intratumoral administration of a TLR3 agonist to activate

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Immunotransplant for lymphoma and solid tumors

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Education

When the Immunology Institute was created in 2007, a central objective of the Institute was to educate and train the next generation of immunologists. A key component of this objective is the development of a PhD training program dedicated to immunology. Prior to 2007, PhD students training in immunology labs were part of a big umbrella training area known as Mechanism of Diseases and Therapy (MDT) and there was no formal training in immunology as a discipline. Thus in 2007, the creation of a separate training area for Immunology was proposed by the leadership of the Institute and was approved by the Graduate School. The curriculum that developed encompasses basic courses in molecular, cellular and system biology in the first year, which then progresses to immunology-specific courses starting the second year. Goal The goal of the IMM training area is to provide students interested in immunology with a rigorous and flexible program. Students will be given the individual intellectual and technical skills required to become outstanding scientists in the field of immunology. By bringing students in various immunology labs into a single training area, the students get together at least twice a week for educational activities. In addition to the educational objectives, these forums also enable the exchange of scientific ideas and knowledge amongst the students. Team The IMM training area is led by two Co-Directors, Dr. Adrian Ting and Dr. Konstantina Alexandropoulos. One of the CoDirectors will chair the qualifying and thesis proposal exams of all IMM students. Through this arrangement, the Co-Directors keep fully abreast of the progress of each individual student. The Co-Directors are assisted by a Steering Committee that consists

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of 6 other faculty plus two student representatives. The role of the Steering Committee is to provide suggestions and advice to the Co-Directors to enhance the training and educational experience of the IMM students. Program The course requirements include the basic Biomedical Sciences I and II courses as well as a minimum of two immunology courses: Fundamentals in Immunology (Fall semester) and Advanced Topics in Immunology (Spring semester). In Fundamentals in Immunology students will get a general yet in depth overview of the immune system through a lecture based course. Several faculty members with different expertise in specific areas of Immunology participate in the course. The Advanced Topics in Immunology course that follows the Fundamentals course will offer students a guided discussion class that reviews current literature in three major areas of immunology. The Advanced Topics course will cover different materials every year and students who wish to take this course more than once are free to do so. Laboratory rotations and research training allows students to rotate and select any of the multiple laboratories that are currently working in immunology, which include allergy, immunology of infectious disease, inflammation, immunodeficiency, autoimmunity, mucosal immunity and transplantation among others. Research groups in the Immunology Institute are using multiple approaches and different model systems to understand how the immune system works, how it is regulated and its function is defective in the context of disease. Numerous laboratories are working in close collaboration with the Mount Sinai Hospital and clinical investigators to develop a clear understanding of the role of the immune system in various diseases with a focus on translational research.

Students will also participate in an Immunology Journal Club, Work in Progress and Seminar Series. The Journal Club will provide the means for students to interact with each other in a small scientific forum. During Work-in-Progress, their work will be evaluated and critiqued by their peers, which include other students, postdocs and faculty members from the Immunology Institute. The seminar series will give them the chance to bolster their knowledge of immunology through a formal seminar with invited speakers as well as an informal lunch session with the speakers. Students in the immunology training area will also be encouraged to participate in the training activities of other

multidisciplinary training areas with overlapping interest such as those in Microbiology, Cancer Biology, Genetics and Genomic Sciences. Similarly, students from all the training areas are welcome to participate in any of the immunology training activities. After completing the immunology training program students will be prepared to continue their careers in basic and/or translational research, and will be able to compete effectively for the best postdoctoral training opportunities in both academia and industry.

This is a comprehensive introductory course to cellular and molecular immunology. It is taught by several faculty members with expertise in different aspects of Immunology and is updated each year to accommodate increasing knowledge in the field. See Appendix II for the class schedule. Advanced Topics in Immunology The advanced topics course highlights specific areas of immunology for in depth study. This is organized as a series of interactive seminars where students are given current papers to read, present and discuss in a focused fashion. The course consists of three different modules that can be taken together or independently. Students must take Fundamentals in Immunology, or have taken a comparable course, before they can register for Advanced Topics. See Appendix II for class schedule. Immunology Journal Club This course follows an intensive small group discussion format that critically evaluates original research articles in the area of immunology. The articles are selected by the presiding faculty member, and include recent important advances in immunology or investigations that provide conceptual advances relating to long-standing problems. This class is required for students beginning their second year until they successfully pass their thesis proposal exam. First year students

interested in immunology are encouraged Attendance is required for all classes.

to

attend.

Immunology Seminar Series This seminar series features presentations by prominent leaders in the field of Immunology, and is attended by all faculty, postdocs and student members of the Immunology Institute. Speakers are either from the US or abroad. Post-docs and students are strongly encouraged to meet with invited seminar speakers during an informal luncheon scheduled for that day. Students are expected to familiarize themselves with the speaker’s research areas. See Appendix III for seminar schedule. Immunology Work in Progress Seminars This seminar series is conducted on a weekly basis, and provides a forum for both students and post-docs to present their own research work to colleagues and mentors within the Immunology Institute. Students are required to attend all Work in Progress seminars. Students will be required to present a 25minute seminar annually, beginning at the end of their 2nd year. The work-in-progress aspect of the presentation is emphasized and final polished studies are not expected. Students are expected to leave a 5-minute period at the end of their presentation for questions and discussions. Advanced Immunology Boot Camp All the students are required to attend the Advanced Course in Immunology offered by the American Association of Immunologists. This is a one-week intense and rigorous course that students take during the summer after their second year in the program.

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Immunology Institute Retreat Members of the Immunology Institute including faculty, students and postdoctoral fellows meet at an off-campus venue for a day during the fall semesters to interact scientifically and socially within an informal setting. Several students and postdocs give oral presentations following selection of their abstracts by screening faculty, whereas all participating students are required to present posters describing their current research. Achievements From its inception in 2007 to June 2014, 17 students will have defended their PhD theses. 8 of these students were in the PhD track and 9 were in the MSTP track. Currently, there are 18 students in the program consisting of 11 in the PhD track and 7 in the MSTP track. Our PhD students have published first-author papers in JI, JEM, JCI, Immunity, Nature Immunology, Nature Medicine, Nature and Cell. Future Over the last 7 years, the quality of our graduate students have steadily improved, in line with the improvement we have seen institutional wide. We aim to make IMM an even more competitive program by recruiting outstanding candidates. We are also developing 'specialized concentration' areas of study in conjunction with other training areas. For example, in collaboration with the Cancer Biology (CAB) training area, we are developing a curriculum in tumor immunology in which both IMM and CAB students can participate. The goal of this particular interaction is to train PhD students such that they become well versed in both tumor-intrinsic processes leading to

cellular transformation, as well as tumor-extrinsic interaction with the immune system post-transformation. We envision developing more such 'specialized concentrations' with other

50

training areas including Microbiology, Genetics and System Biology.

Adrian Ting received his PhD in Immunology from the Mayo Graduate School/Mayo Clinic in Rochester, MN. He conducted his postdoctoral training in the Department of Molecular Biology at Massachusetts General Hospital in Boston, MA. He is currently an Associate Professor of Medicine/Clinical Immunology at the Icahn School of Medicine at Mount Sinai in New York. He has been a Co-Director of the Immunology Training Area for the PhD program since its inception in 2007. He is currently a member of the NIH Cellular & Molecular Immunology-A (CMI-A) study section.

Caspase-8 function's as a survival molecule

Research Interests

Excessive cell death in the gut and skin epithelium results in inflammation. Dr. Ting's lab is studying how TNF and its regulation of CYLD affects inflammation. Since dysregulation of TNF causes inflammatory disorders such as psoriasis and IBD, his lab is currently examining the role of CYLD, RIP1 ubiquitination and cell death in animal models of inflammation. Concurrently, tissues from patients with inflammatory disorders are being examined for dysregulation of these molecular mechanisms of cell death. The goal is to thoroughly characterize the regulation of these cell death pathways so that drugs can be rationally designed to modulate these pathways for therapeutic purposes in inflammatory diseases.

Ubiquitination of RIP1 as a cell death checkpoint Dr. Ting's lab is interested in how ubiquitin modification affects cellular survival and death, and in turn how life and death decisions affect inflammation. One focus of his studies is the role played by ubiquitination of the TNFR1 signaling molecule RIP1. His laboratory made the discovery that non-canonical K63-linked polyubiquitination of RIP1, or the lack thereof, determines whether cell survival or apoptotic cell death ensues in response to TNF.

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More recently, Dr. Ting's lab also discovered that ubiquitination has a major role in regulating an inflammatory form of cell death known as necroptosis. They made the observation that Caspase 8 has a pro-survival function (contrary to its well established role in causing apoptosis) via the cleavage of the tumor suppressor CYLD to suppress necroptosis. CYLD is a deubiquitinase enzyme that removes K63-linked polyubiquitin chains from target proteins including RIP1. Deubiquitination of RIP1 by CYLD is necessary for necroptosis and removal of CYLD by Caspase-8 sustains RIP1 ubiquitination and cell survival. Regulation of inflammation by cell death pathways

Konstantina Alexandropoulos received her Ph.D. in Molecular Biology from the City University of New York (CUNY), USA. She did her postdoctoral training in Dr. David Baltimore’s laboratory at Rockefeller University and Massachusetts Institute of Technology (MIT). After her postdoctoral training she worked for 10 years as an Assistant Professor at the College of Physicians and Surgeons, Columbia University Medical Center. She is currently Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York. She is the co-Director of the Immunology multidisciplinary training area; course Director/Lecturer for Immunology training area-related courses, and Adjunct Lecturer at Drexel University Medical School. She serves in a number of Institutional committees including admissions committees for the MD/Ph.D and Ph.D programs, faculty recruitment committees and Immunology MTA Steering committee. She became elected member of the Henry Kunkel Society in 2013. Research Interests Mechanisms of Central Tolerance and T cell mediated Autoimmunity We are studying the role of medullary thymic epithelial cells (TECs) in establishment of T cell tolerance using conditional knockout mice. We have shown that conditional depletion of mTECs leads to development of autoimmune hepatitis (AIH)

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that recapitulates all known histopathological and immunological characteristics of the human disease (JCI, 2013). We are currently exploring the mechanisms leading to disease development and developing novel therapeutic approaches for managing/treating AIH. Regulation of thymic dendritic cell populations by thymic stromal cells We recently found that in addition to regulating central T cell tolerance, mTECs also control the intrathymic development of specific dendritic cell (DC) subsets as well as recruitment of peripheral DCs into the thymus. We are interested in elucidating the unique and/or overlapping contributions of mTECs and thymic DCs in the generation of the effector and regulatory T cell repertoires in the thymus as well as in peripheral autoimmunity. Role of the T cell repertoire in mucosal inflammation and composition of the intestinal microbiota In recent studies we explored whether disturbances in the T cell repertoire lead to disruptions in mucosal homeostasis. We found that altered T effector and T regulatory cell repertoires resulting from aberrant T cell selection in the mTEC-depleted thymus associate with development of colitis in genetically susceptible mice. This is accompanied by disturbances in the colonic bacterial load and composition suggesting that host genetics (T cell repertoire) can influence host microbiota and regulate mucosal inflammation within the context of an otherwise normal mucosal environment.

February 12 March 12 April 2 May 14 June 11 July 9 August 13 September 10 November 12 December 10

Michael Overholtzer

2013

2011 January 11 February 8 March 8 April 12 May 10 June 14 July 12 August 9 September 13 October 11 November 8 December 13 2012 February 14 March 6 March 13 April 10 May 8 June 12 July 10 August 14 September 13 October 9 November 13

APPENDIX IV Immunotherapy Studies Study Title Immune Modulators: NY-ESO-1 Vaccine in combination with Imiquimod NY-ESO-1 Vaccine in combination with Resiquimod and Montanide NY-ESO-1 Vaccine in combination with PolyICLC and Montanide NY-ESO-1 long peptide in combination with Poly-ICLC and Montanide In Situ Vaccine for Low-Grade Lymphoma: Combination of Intratumoral Flt3L and PolyICLC With Low-Dose Radiotherapy Treatment of Solid Tumors With Intratumoral Hiltonol® (Poly-ICLC) NY-ESO-1 protein-DEC-205 vaccine with PolyICLC and Flt3L Dendritic Cell Vaccine: DC with NY-ESO-1 and Melan-A/MART-1 long peptide and Poly-ICLC

measured by flow cytometry 75 mAb with specificity for LILRB members produced that bind to receptors on cell surface More than 50 mAb with specificity for virus have been generated from human blood.

Bait being produced to sort cells from subject samples

80 mAb produced, affinity measured, binned by specificity using Octet analysis and ELISA generated and validated. Institutional “Request Panel of 50 monoclonal for Target” initiated antibodies produced and project. NIH funding tested. Many show applications specificity for HPV tumors submitted. including those derived from cervical tissue. NIH funded project Using unique vesicle immunization strategy mAb with specificity for TACI short were produced

Agonist and antagonists testing of mAb underway. Both types identified in preliminary assays Neutralization assays are underway with some positives identified.

Development phase

Luminex style assay is in development.

Testing for function of antibodies on panels of HPV tumor cells. Lead candidate identification underway. Testing of mAb function underway. Additional mAb are in development

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Appendix V Biosketches

APPENDIX III BIOSKETCHES BIOGRAPHICAL SKETCH NAME Alexandropoulos, Konstantina EDUCATION/TRAINING INSTITUTION AND LOCATION Mercy College, Dobbs Ferry, New York Hunter College, City University of New York A. Personal Statement Dr. Alexandropoulos has been an investigator at the Mount Sinai School of Medicine since July 2008 when she was appointed as an Associate Professor. Over the past several years the Dr. Alexandropoulos’ research has focused on elucidating signaling mechanisms that regulate the function of T lymphocytes. Recently her research focus has been on thymic epithelial cell development and how mutations that affect the function of these cells regulate T cell development and function. The PI has accumulated expertise with purifying, staining and analyzing thymic epithelial cell populations, T cells from many tissues, immunohistochemical assays, assaying for autoimmune manifestations, T cell-mediated immune responses and studying signaling pathways in these cells. This expertise is relevant and will be applied towards the experiments described in this application. B. Positions and Honors Positions:

79

POSITION TITLE Associate Professor DEGREE B.S. Ph.D.

YEAR(s) 1986 1992

FIELD OF STUDY Biology Molecular Biology

1984-86: Research Assistant (during undergraduate studies), laboratory of Dr. Lola Margolis, New York Medical College, Valhalla, New York 1987-92: Graduate student, laboratory of Dr. David Foster, Hunter College, City University of New York 1992-97: Postdoctoral fellow in the laboratory of Dr. David Baltimore, Rockefeller University, New York (1992-94) and Massachusetts Institute of Technology, Cambridge, Massachusetts (1994-97) 1997-6/08: Assistant Professor, Department of Pharmacology, College of Physicians & Surgeons, New York 7/08-present Associate Professor, Department of Medicine, Immunology Institute, Mount Sinai School of Medicine Honors: B.S., Magna cum laude; M.S./Ph.D., Magna cum laude Scholarship and Welfare Fund of the Alumni Association of Hunter College The Frederick Velergakis Graduate Award

EDUCATION/TRAINING INSTITUTION AND LOCATION Wellesley College, MA New York University School of Medicine New York University School of Medicine New York University School of Medicine A. Personal Statement Dr. Bhardwaj is the Director of Immunotherapy and the Medical Director of the Vaccine and Cell Therapy Core facility. She is an expert on human dendritic cell (DC) subsets, specifically with respect to their isolation, biology, function and use as vaccine adjuvants in humans. She has been principal investigator for the design and implementation of several clinical trials studying novel experimental immunotherapies for melanoma and other cancers using TLR agonists or dendritic cells as adjuvants. Her lab also investigates DC biology in the tumor microenvironment as it relates to anti-melanoma immunity. B. Positions 1981 - 1982 Internship; Internal Medicine, Brigham and Womens Hospital, Boston, MA 1982 – 1984 Residency; Internal Medicine, Brigham and Womens Hospital 1986 - 1989 Post-doctoral Associate, Laboratory of Cellular Physiology & Immunology, Rockefeller University, New York, NY 1989 - 1998 Research Assistant Professor (non-tenure track), Rockefeller University 84

POSITION TITLE Professor of Medicine, Division of Hematology and Medical Oncology Director, Immunotherapy Program DEGREE B.A. M.S. M.D. Ph.D.

BIOGRAPHICAL SKETCH NAME Blander, Julie Magarian EDUCATION/TRAINING INSTITUTION AND LOCATION American University of Beirut, Beirut, Lebanon University of California Los Angeles, Center for the Health Sciences, Los Angeles, CA University of Pittsburgh School of Medicine, Department of Molecular Genetics and Biochemistry, Pittsburgh, PA Yale University School of Medicine, Department of Immunobiology, New Haven, CT A. Personal Statement My previous work and training in the laboratories of Olivera Finn, Charles Janeway and Ruslan Medzhitov have allowed me to gain extensive experience in tumor immunology, CD4 and CD8 T cell differentiation in mouse and human systems, DC biology, phagocytosis, and antigen presentation, as well as dissection of Toll-like receptor and Nod-like receptor signaling pathways. Our studies have led to several high impact publications, and have made significant impact in the fields of innate and adaptive immunity. B. Positions and Honors Positions and Employment 1986-1988 Clinical Laboratory Assistant, Department of Laboratory Medicine, Central Specimen Processing, University of California Los Angeles, Center for the Health Sciences. 1988-1991 Clinical Laboratory Technologist, Department of Laboratory Medicine, Clinical Virology Laboratory, University of California Los Angeles, Center for the Health Sciences.

1977-1979 Visiting Scientist, Laboratory of Immunology, MAID, NIH, Bethesda, MD 1979-1981 Associate Professor, Department of Microbiology, Mount Sinai School of Medicine, NY 1982-2011 Professor, Department of Microbiology, Mount Sinai School of Medicine, NY 1985 Visiting Professor, Department of Biology, MIT, Cambridge, MA (Jan – July) 1996-1997 Visiting Professor, Institute of Genetics and Molecular Biology, Kyoto, Japan 2011-present Professor Emeritus, Icahn School of Medicine at Mount Sinai, NY Scientific Societies 1968 Elected Member of International Society of Cell Biology Elected Member of Board of Governors of the European Cell Biology Organization 1969 Elected Member of French Society of Immunology, Paris Elected Member of Royal Microscopial Society, Oxford Elected Member of Reticuloendothelial Society, USA

Nominated Member of the Board of European Group for the Study of Lysosomes, Louvain 1970 Elected Member of Royal Society of Medicine, London 1971 Elected Member of French Society of Electron Microscopy, Paris 1973 Elected Member of British Society of Immunology 1978 Elected Member of American Association of Immunology 1980 American Society of Zoologists The New York Academy of Sciences 1985 Elected Member of The Harvey Society 1991 Honorary Member of Romanian Immunology Society 1992 Elected Member of Romanian Academy 1998 President of Romanian Society for Immunology 2004 American Academy of Microbiology Professional Organizations Ad hoc reviewer National Science Foundation (Cell Physiology Program) American Cancer Society NIH – Allergy and Immunity Study Section, Program Project: Autoimmunity National Fund for Scientific Research, Belgium Foundation for Medical and Health Research Council, Canada Arthritis Foundation, Devil’s Bag Award Medical Council, Canada National Cancer Institute National Institute of Allergy and Infectious Diseases Veteran Administration National Health and Medical Research Council, Commonwealth of Australia Canadian Arthritis Foundation US-Israel BiNational Science Foundation, Jerusalem

A. Personal Statement I have extensive experience in conducting trials of intratumoral TLR-based in situ vaccination and developing immune correlative studies: NCT00185965 {Brody et al., J, Clin Oncol 2010}, NCT00226993{Kim et al., Blood 2012}, NCT00880581, and NCT01396018. As Director of the Lymphoma Immunotherapy Program at Mount Sinai School of Medicine, I also have available resources and a substantial cohort of eligible patients to rapidly and fully accomplish the goals of the proposed study. The Brody Lab focuses on pre-clinical and clinical development of novel vaccine and adoptive T cell transfer approaches to treat patients with lymphoma and hematologic malignancies. Specifically, current projects including work on an in vitro high throughput combinatorial survey of a panel of TLR agonists for activation of PBMC, cutaneous APC, and B-cell lymphomas- this project has potential application to the proposed Research Plan if we observe insufficient activation of intratumoral Flt3L-recruited DC using poly-ICLC, future iterations can utilize the alternatives determined to be more effective from this project B. Positions and Honors

Identification of Novel Prostate Adenocarcinoma-Produced Dendritic Cell Suppressors by Gene Expression Profiling Focus on tumor-induced inhibition of monocyte derived DC IL-12 production and surface co-stimulatory molecule expression in response to Toll-Like Receptor agonists 1998: Proposal design at S.U.N.Y. S.B. Dept. of Biochemistry with Dr. Sanford Simon Development of plasmid encoding single-chain, intracellularly expressed monoclonal antibodies under the control NK- κB. Focus on anti-NF-κB scFv cDNA isolation from B cell library phage display selection. 1994-6: Research associate at Dana Farber Cancer Institute Department of Tumor Immunology with Dr. Christopher Rudd Signaling and trafficking of the CD28 Costimulatory Molecule. Activation mechanisms of the HIV-LTR promoter by CD28. Focus on correlation of CD28 costimulatory function and trafficking stage in wild-type and PI3-K binding mutants. Also published in Harvard University Dept. of Molecular and Cellular Biology archival collection. 1994: Research associate at NYU Dept. of Biochemistry with Dr. Michel Blumenfeld Analysis of cis- and trans- elements of the keratin 17 and involucrin promoters. Focus on preparation of the promoters for these markers and isolation of the trans- binding elements for the purpose of determining transcription factors culprit in the malignant transformation. Other Experience and Professional Memberships 2013 --Alliance For Clinical Trials in Oncology. 2012 --Society for the Immunotherapy of Cancer 2007 --American Association of Cancer Research, associate member 95

BIOGRAPHICAL SKETCH NAME Brown, Brian D. EDUCATION/TRAINING INSTITUTION AND LOCATION University of Guelph, Guelph, Ontario, Canada Queen’s University, Kingston, Ontario, Canada Hospital San Raffaele, Milan, Italy A. Personal Statement My laboratory is focused on identifying factors that control the innate immune system in different disease conditions, and in response to particular drugs, including gene-based medicines. In collaboration with the Merad lab in the Mount Sinai Immunology Institute, we have carried out detailed work to decipher the transcriptional programs that control dendritic cell development and function, which included profiling and analysis of more than 200 different populations of immune cells (Miller et al. Nature Immunology 2012), and to identify the mechanisms involved in the host response to HIV and HIVderived vectors (Brown et al. Blood 2007, Agudo et al. Molecular Therapy 2012). More recently, we identified a new pathway controlling the type I interferon response to pathogen-associated nucleic acids and HIV, which involves the microRNA miR-126, and the main VEGF receptor, VEGFR2 (Agudo et al. Nature Immunology 2014). We are now investigating how miR-126/VEGFR2 control of the innate immune system impacts tumor growth. In addition to our work on innate immunity, we are studying some of the fundamental aspects of microRNA biology. Specifically, we are trying to understand how microRNAs and their targets interact and the consequences of this interaction. We were amongst the first to show that the target of a 97

POSITION TITLE Associate Professor DEGREE B.Sc. Ph.D.

MM/YY 1993 - 1997 1998 - 2003 2003 - 2007

FIELD OF STUDY Biomedical Science Pathology Molecular Medicine

microRNA can ‘sponge’ the microRNA and inhibit its activity (Brown et al. Nat Biotech 2007). This finding led to the development of microRNA sponge/decoy vectors, which is a seminal technology that enables inhibition of a microRNA within a cell and loss-of-function analysis (Brown and Naldini. Nat Rev Gen 2009). We subsequently uncovered one of the mechanisms responsible for the sponging phenomenon, which involves a negative feedback mechanism whereby target regulation results in uridylation of a microRNA and this mark accelerates the microRNA’s rate of decay (Baccarini et al. Curr Biol 2011). We are now working to understand how endogenous sponging that is mediated by a newly discovered class of RNAs, called circular RNAs, impacts cell regulation and oncogenesis. B. Positions and Honors Academic Appointments 2013 – Present Associate Professor, Icahn School of Medicine at Mount Sinai, New York, NY Department of Genetics and Genomic Sciences 2012 – Present Faculty, Tisch Cancer Institute 2012 – Present Faculty, Diabetes, Obesity and Metabolism Institute 2012 – Present Faculty, Mindich Child Health and Development Institute

EDUCATION/TRAINING INSTITUTION AND LOCATION Lehigh University, Bethlehem, PA Queens College, Flushing, NY Albany Medical College Albany, NY N.Y. Hospital-Cornell Med. Center, NY N.Y. Hospital-Cornell Med. Center, NY A. Personal Statement Dr. Burakoff is the Director of the Tisch Cancer Institute, and has extensive administrative experience, having served as Director of the New York University Cancer Institute (NYUCI) at the New York University School of Medicine (NYUSM) from 2000-2007, as well as the Director of the Skirball Institute of Biomolecular Medicine at New York University from 20002006; former Chair of the Department of Pediatric Oncology at the Dana-Farber Cancer Institute from 1985-2000; and in his current position as a member of the external advisory boards of four NCI-designated cancer centers. He has been a member of the American Cancer Society’s Council of Extramural Grants, and sits on the Damon Runyon Cancer Research Foundation Board of Directors. Dr. Burakoff also has over 30 years of experience in immunological research. His research has focused on the role of the T cell in the immune response and he has been one of the most highly cited researchers in Immunology for over 25 years.

A. Personnel Statement My research has focused upon asthma and Hereditary Angioedema (HAE). I have investigated factors, including age, which affects the chronic airway inflammation in asthma. My K08 funding centered upon the role of TNF-a in airway mucus metaplasia in mouse models of asthma. As an internist and a T. Franklin Williams Scholar (program developed by the Association of Specialty Professors for young physicianscientists focusing study on gerontological aspects of their speciality), my research expanded to the study of asthma in older patients. To accomplish this goal, my laboratory developed and characterized a murine model of allergic asthma using aged mice. To expand these studies into human disease, I have evaluated atopic and clinical characteristics in a cohort of older patients with asthma. In addition, I have developed skills and experience in clinical research, in particular for treatment of HAE. I provide care to over 40 patients with HAE and have begun laboratory work to investigate mechanisms by which estrogen may exacerbate HAE.

105

POSITION TITLE Associate Professor of Medicine, Division of Clinical Immunology

B. Positions and Honors Professional Positions 1996-1999 Intern and Resident-Internal Medicine, Mount Sinai School of Medicine, New York 1999-2001 Fellowship in Allergy and Immunology, Mount Sinai School of Medicine, New York 2001-2004 Instructor of Medicine, Division of Clinical Immunology-Mount Sinai School of Medicine 2005-2006 Director, Allergy and Asthma Clinic, Mount Sinai Hospital 2004- Assistant Professor of Medicine, Division of Clinical Immunology-Mount Sinai School of Medicine 2006- Assistant Professor of Medicine, Immunology InstituteMount Sinai School of Medicine 2013- Associate Professor of Medicine, Mount Sinai School of Medicine Awards and Other Professional Activities: 1993 Summer Medical Student Intramural Research Fellowship (N.I.H.)

BIOGRAPHICAL SKETCH NAME Chen, Benjamin K. EDUCATION/TRAINING INSTITUTION AND LOCATION Stanford University, Stanford, CA Rockefeller University, New York, NY Mentor: David Baltimore Weill College of Medicine of Cornell, New York, NY Whitehead Institute for Biomedical Research, Cambridge, MA Mentor: Peter S. Kim A. Personal Statement Dr. Chen’s research career has focused on HIV-host cell interactions that support viral replication. The work from his laboratory has focused on how the assembly and production of HIV in T cells is regulated by the cell-cell contacts and how these contacts called virological synapses (VS) enhance infection. The laboratory has designed recombinant forms of infectious HIV that facilitate measurement of the steps of the virus life cycle. Utilizing fluorescently tagged HIV clones and live microscopy his laboratory revealed that cell adhesion induced by the viral Env protein induces the active recruitment of assembling virus particles to the cell-cell junction. With live 3dimensional confocal microscopy methods, the laboratory was the first to capture the dynamic directional movement of the viral structural protein Gag into the VS. This work revealed a novel endocytic entry pathway that is mediated by the VS. The laboratory has discovered that cell-mediated HIV infection is a more efficient mode of infection, resistant to patient neutralizing antibodies, and the predominant mode of infection 111

POSITION TITLE Associate Professor DEGREE B.A.S.

MM/YY 06/90

FIELD OF STUDY Biology & Philosophy

Ph.D.

05/98

Molecular Virology

M.D.

05/99

Medicine

Post doc

Biochemistry/Virology

in vitro. We have found that infection through the VS can result in the simultaneous transmission of multiple genetic copies of HIV, making HIV functionally multiploid. This mode of inheritance may explain the ability of HIV to tolerate high levels of genetic diversity. Recent work also suggests that the regulation of Env fusogenicity during infection through the VS mediates resistance of VS to neutralizing antibodies. Thus the VS may be an important vaccine target in the future. In addition to studying the mechanisms of the synapse formation, current studies in the laboratory have also focused on the role of cellto-cell infection in a parenteral model of HIV transmission in humanized mice. The goal of these studies is to visualize VS in vivo and to characterize how they participate in viral spread in vivo. Overall, the studies on VS examine how immune cells actively participate in HIV dissemination providing a new paradigm with which to understand many aspects of HIV pathogenesis. B. Positions and Honors Research Experience/Employment:

BIOGRAPHICAL SKETCH NAME Chen, Shu-Hsia EDUCATION/TRAINING INSTITUTION AND LOCATION Shoo-Chow Univ., Taiwan, ROC Nat’l Yang-Ming University, Taiwan, ROC Nat’l Yang-Ming University, Taiwan, ROC A. Personal Statement My lab is interesting on the mechanism of myeloid derived suppressor cells (MDSC) and T regulatory cells (Treg) mediated immune suppression in tumor microenvironment, and the control of myeloid cells differentiation into to M1 vs. M2 macrophage, which may facilitate the intervention of cancer immune therapy and control tumor inflammation and metastases. I have the expertise and motivation that are necessary to serve as a mentor for this grant application. I have a broad background in cancer biology, immune therapy, and immune tolerance, with specific expertise in the area of MDSC-mediated immune suppression, Treg regulation and macrophage differentiation. As a senior immunology faculty member at Mount Sinai School of Medicine, New York, I carried out several pioneer studies in immune modulatory therapy and the mechanisms behind immune suppression mediated by myeloidderived suppressor cells (MDSC) and their multiple suppressive functions in the regulation of host immunity. I have broadspectrum knowledge on the topic of MDSCs enabling me to provide the proper intellectual guidance to ensure the trainees’ success in their project and help them establish their independence. I have trained more than 20 research fellows and students, and currently have over 12 former fellows, which have 115

POSITION TITLE Professor DEGREE B.S. M.S. Ph.D.

MM/YY 07/85 07/87 07/92

FIELD OF STUDY Microbiology Microbiol. and Immunol. Microbiol. and Immunol.

gone on to become faculty and conduct their own independent research internationally. In addition, I have considerable experience in conducting clinical translational work and moving basic research to clinical application. I have been continuously supported by multiple NIH funded research grants in both preclinical basic researches and clinical trials. I also served as a regular NIH reviewer on the panel for the TTT (transplantation, tolerance, tumor immunology) study section, which is indicative of my scientific training and expertise in immune modulation therapy in cancer and immune tolerance area. I will utilize my expertise, training experience, and leadership to assist in the success of these trainees. In summary, I have demonstrated my track record of training multiple students and fellows in becoming independent investigators, have successful and productive research and my expertise and experience qualify me as the mentor for this application. B. Positions and Honors Positions and Employment 1992-1995 Research Associate, Howard Hughes Medical Institute/Department of Cell Biology, Baylor College of Medicine, Houston, Texas 1995-1996 Assistant Professor, Department of Cell Biology, Baylor College of Medicine, Houston, Texas

1997-2004 Assistant Professor, Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York 2005-2010 Associate Professor, Dep. Gene and Cell Medicine, Dep. of Oncological Science, Dep. General Surgery, Mount Sinai School of Medicine, New York, New York 2010-present Professor, Dep. Oncological Sciences, Dep Surgery, Mount Sinai School of Medicine, New York, NY Other Experience and Professional Memberships 1995Active Member, American Association for Cancer Research 1995- Active Member, American Association of Immunologist 1999, 2001 Grant reviewer for RAID program, NCI. 2003 Grant reviewer in Experimental Immunology study section, NIH. 2005 Ad Hoc member for Center for Scientific Reviewer in Transplantation, Tolerance and Tumor Immunology (TTT) study section, NCI, NIH. 2005 Ad Hoc member in Center for Scientific Review for Special Emphasis Panel, NIH. 2005 Ad Hoc member in Clinical Research Review Committee for National Center for Research Resources (NCRR), NIH. 2007 Scientific Reviewer for Department of Defense (CDMRP), Prostate Cancer Research Program 2008 Scientific Reviewer for Department of Defense (CDMRP), Breast Cancer Research Program. 2009 Scientific Reviewer, Department of Defense (CDMRP), Prostate Cancer Research Program (PCRP), the Idea Development Award (IDA) and Synergistic Idea Development Award (SIDA). 2006-2009 Regular Member in Center for Scientific Review of Transplantation, Tolerance and Tumor immunology (TTT) study section, NIH.

BIOGRAPHICAL SKETCH NAME Clemente Litran, Jose Carlos EDUCATION/TRAINING INSTITUTION AND LOCATION Universidad de Sevilla (Spain) Japan Advanced Institute of Science and Technology (Japan) Japan Advanced Institute of Science and Technology (Japan) A. Personal Statement High-throughput sequencing technology is providing increasing amounts of data that must be turned into actionable knowledge in the clinic, the laboratory and the field. Studies of the microbiome in particular have greatly benefited from this flow of information, allowing us to understand the true extent of microbial diversity in the human body. These studies have provided us with a baseline characterization from which we can now tackle more relevant questions on the relation between disease and imbalances in the microbiome. I have a broad background in computer science and bioinformatics, with specific training and expertise in the analysis of microbiome data, as demonstrated by my collaboration in several high-profile studies characterizing the microbiome across body sites (HMP 2012a; HMP 2012b), along time (Pantoja-Feliciano, Clemente, et al., 2012), and populations (Yatsunenko et al 2012). I am one of the main developers of QIIME (Caporaso et al., Nat Methods 2010), the BIOM format (McDonald, Clemente et al., 2012) and PICRUSt (Langille et al., 2013), widely used tools for the analysis of microbial community data. In summary, I have a demonstrated record of accomplished research projects as shown by my strong 122

POSITION TITLE Assistant Professor DEGREE B.Sc.

MM/YY 09/00

FIELD OF STUDY Computer Science

M.Sc.

03/04

Bioinformatics

Ph.D.

03/07

Bioinformatics

publication record and my contributions to the development of tools and protocols for the analysis of microbiome data, which have prepared me to contribute critically to the success of this project. B. Positions and Honors Positions and Employment 2007-2010 Japan Society for the Promotion of Science postdoctoral fellow, National Institute of Genetics (Japan). 2010-2012 Research Associate, Department of Chemistry and Biochemistry. University of Colorado. 2013-present Assistant Professor, Department of Genetics and Genomic Sciences, and Department of Medicine. Mount Sinai School of Medicine. Honors 2007 Best Ph.D. thesis award. Japan Advanced Institute of Science and Technology, School of Knowledge Science. C. Selected Peer-Reviewed Publications (selected from 36 peer-reviewed publications) Most relevant to current application 1. Leopoldo N. Segal, Alexander Alekseyenko, José C. Clemente, Rohan Kulkarni, Benjamin Wu, Samuel Chung, Kenneth Berger, Roberta Goldring, William N. Rom, Constantin

D. Research Support Completed Research Support Japan Society for the Promotion of Science (PI: Clemente) 20082010 Kaken-hi Research Grant [ID: P08086]: “Mechanisms of evolution of metabolic pathways: characterization in green sulfur bacteria metabolism and xenobiotic degradation pathways” The goal of this project was to study mechanisms of metabolic pathway evolution utilizing two models of particular interest: green sulfur bacteria and bacterial pathways of xenobiotic degradation. This study resulted in the development of an optimized method to reconstruct ancestral states, which allowed us to work with larger datasets at a fraction of the computational cost. National Institute of Genetics (Japan) (PI: Clemente) 20112012 Collaborative Research Grant [ID: B10-2011]: “The Rice Microbiome Project” The goal of this project was to characterize the evolution of bacterial communities in bulk soil and rhizhosphere of four different rice cultivars, from seedling to harvest. We are currently characterizing how the changes observed in the microbiome of these rice varieties are related to developmental stage, nutrient conditions, and pH. University of Colorado (PI: R. Knight) 2011-2013 Janus supercomputer allocation grant [ID: UCB00000015]: “QIIME parameter sweep” The objective of this study was to determine the effect that different parameters in the QIIME pipeline have when analyzing microbiome data. In particular, we measured how diversity estimates, taxonomic assignment, and predictive accuracy are affected by the particular choice of parameter values in QIIME.

A. Personal Statement Over the past 20 years I have set up in Lille (France) together with my colleagues a successful comprehensive research and health care network fully dedicated to Inflammatory Bowel Diseases (Crohn’s disease [CD] and ulcerative colitis [UC]). Our research centre was composed of 3 complementary groups: (1) a medical and surgical department which has performed many multicentre studies at the national (GETAID group) and international level; (2) an epidemiological group based upon the IBD North-Western Registry (EPIMAD); (3) a physiopathological group devoted to the study of immunological mechanisms and the development of new therapeutic targets in regulation of digestive inflammation. Thanks to the development of multiple local, national and international collaborations we have been able to make some important contributions to the pathophysiology of IBD. The most remarkable are the initiation in 1994 of collection and sampling of IBD families that eventually led to the identification of NOD2 as a susceptibility gene for CD, the development in the 90’s of the ASCA test (antiS. cerevisiae (mannan) antibodies) which is still the most sensitive and specific serologic marker for CD and elucidation of the potential role of Candida albicans in CD and the identification of a new pathovar of Escherichia coli (AIEC for 125

adhesive invasive E.coli) associated with ileal CD. At the national level, I have been one of the leaders of the GETAID group, initiating and participating to many clinical trials that have helped to improve therapeutic strategies in IBD especially regarding the use of immunomodulators and biologics. Apart from international recognition, one of the biggest achievement of the GETAID has been the emergence of a new generation of young and bright European gastroenterologists with an interest in IBD. At the international level I have been involved as participant or primary investigator in most recent therapeutic trials with biologics. The main concretisation of this work has been the publication as primary author or co-author of more than 500 peer-reviewed papers and 30 chapters of books most of them in the domain of IBD. I have been invited to give talks in many countries either during IBD meetings or national and international meetings including UEGW and DDW. I have been and am still in the editorial board of several gastroenterology journals including Clinical Gastroenterology and Hepatology, Nature reviews in Gastroenterology and Hepatology, Inflammatory Bowel Disease and Journal of Crohn’s and Colitis. I have been associate editor of Gut from 2005 to 2009 and I am currently associate editor of Alimentary Pharmacology and Therapeutics being in charge of

BIOGRAPHICAL SKETCH NAME Cortes, Patricia EDUCATION/TRAINING INSTITUTION AND LOCATION Universidad Austral, Chile Universidad Austral, Chile UMDNJ-Robert Wood Johnson Medical School, NJ A. Personal Statement My laboratory investigates the mechanism and regulation of V(D)J recombination and DNA repair. Our group was the first to demonstrate that RAG2 C-terminus bridges the RAG recombinase with chromatin through histone interaction. In a more recent study, we showed that mutations in the PHD domain of RAG2, identified in patients with SCID and Omenn Syndrome, affected its stability, cellular localization and histone interaction. My group has also characterized the nuclease activity of the RAG recombinase and contributed to the limited number of publications describing the biochemical properties of full-length RAGs. In the past few years we expanded our studies to investigate the mechanistic and regulatory roles of Artemis and Ligase IV on V(D)J recombination and DNA repair, two processes that are linked by the generation of double strand breaks and the participation of non-homologous end joining proteins in repairing the DNA breaks. Our most recent work demonstrated a key role for Artemis in facilitating efficient V(D)J recombination; a function that is mediated by the interaction of the Artemis C-terminal with DNA ligase IV and DNA-PKcs. An important link between the processing and repair factors of V(D)J recombination and DNA repair was demonstrated by our findings. The Artemis-

POSITION TITLE Associate Professor DEGREE B.S.

YEAR(s) 1981-1984

FIELD OF STUDY Biochemistry

M.S. Ph.D.

1984-1985 1987-1991

Biochemistry Biochemistry and Molecular Biology

DNA Ligase IV interaction was mapped to an 11 aa peptide on Artemis and to the DNA binding domain of DNA Ligase IV. In collaboration with the laboratory of Dr. Aneel Aggarwal, we solved the structure of this complex. In summary, my group has contributed to understanding the mechanism and regulation of V(D)J recombination as well as DNA repair. In addition, we have provided training and career development for numerous postdocs, Ph.D. students, college and high school students. Among a total of 29 trainees (four of which were high school students), 15 were women and 11 were underrepresented minorities. My group has and will continue to educate future generation of scientists while maintaining a strong commitment to research. B. Positions and Honors Positions and Employment 1991-1995 Postdoctoral Fellow, Rockefeller University New York, New York (Dr. David Baltimore) 1995-1996 Postdoctoral Fellow, Rockefeller University

7 128

New York, New York (Dr. Michel Nussenzweig) Research Associate, Rockefeller University New York, New York (Dr. Michel Nussenzweig) Assistant Professor (non-tenure track), Rockefeller University New York, New York (Dr. Michel Nussenzweig’s laboratory) 1999-2010 Assistant Professor, Mount Sinai School of Medicine New York, New York 2010-Present Associate Professor, Icahn School of Medicine at Mount Sinai New York, New York 1982, 1983 and 1984 Undergraduate Scholarship. Award to the Honors and Awards best student of the Science School. Universidad Austral de Chile. 1988 Graduate Fellowship from Hoechst Celanese Corporation. 1989 Graduate Fellowship from the Kirin Brewery Corporation. Postdoctoral Fellowship from the Irvington Institute. 1995-1996 Postdoctoral Fellowship from the Lymphoma Research Foundation of America. 1998-1999 Arthritis Investigator Award from the Arthritis Foundation. 1999-2003 Cancer Research Institute Investigator Award. 2001-2006 The Leukemia and Lymphoma Society Scholar Award. 2004-2008 American Cancer Society Research Scholar Award. 2006-2011 The Irma T. Hirschl/Monique Weill-Caullier Research Award. 1995

EDUCATION/TRAINING INSTITUTION AND LOCATION Duke University, North Carolina Columbia University New York University A. Personal Statement: My career has been based on work on the pathogenesis, characterization and treatment of human immune deficiency diseases. I am a Professor of Medicine, Pediatrics and Immunology at Mount Sinai Medical Center, and Program Director for Allergy Immunology Fellowship Training. I obtained my PhD in immunology, and from this beginning, fortunately found myself in the world of Primary Immune Deficiency, leading to both basic research and clinical care. I am the Principle Investigatory of the USIDNET, an NIH supported research Consortium of the Immune Deficiency Foundation. I am an internist by training but have held a pediatric appointment for many years. I established the Primary Immune Deficiency Clinic at Mount Sinai, a referral service for infants, children and adults with known or suspected primary immune deficiency diseases for the Northeast; however patients come from all over the United States and other countries. We have a long standing laboratory investigation on the defects of human immune cells, based on the genetic defects that occur in these subjects. These studies have proved of great value in

BIOGRAPHICAL SKETCH NAME Stephanie Dahan EDUCATION/TRAINING INSTITUTION AND LOCATION University of Sciences, Nice-France

DEGREE M.Sc.

YEAR(s) 1997

University of Sciences, Marseille-France

Ph.D.

2002

Mount Sinai School of Medicine

Post-doc

2008

A. Personal Statement: I have focused my research on the description of the central role of epithelial cells in homeostasis and disease states. I have extensive expertise in manipulating intestinal epithelial cells and lamina propria lymphocytes isolated from human intestinal resection and studying their molecular crosstalk. In addition, I developed murine models of colitis where permeability and tight junctions played a major role. Thus, I have the required experience to oversee the proposed project. B. Positions and Honors: Research Experience: 1998-2002 Graduate Student, Laboratoire de Gastroentérologie et Nutrition, Nice, France 2004-2008 Postdoctoral fellow, Immunobiology Center, Mount Sinai School of Medicine, New York, USA 2008-2011 Instructor, Immunology Institute, Mount Sinai School of Medicine, New York, USA 2011-current Assistant Professor of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA Honors: 136

POSITION TITLE Assistant Professor FIELD OF STUDY Biochemistry Life Sciences, Cellular and Molecular Nutrition Immunology

1999-2002 Fellowship provided by the Laboratoires Biocodex and the Région Provence-Alpes Côte d’Azur 2002 Travel Award for the Journées Francophones de Pathologies Digestives 2009-2012 Career Development Award granted by the Crohn’s and Colitis Foundation of America (CCFA) 2010 Young Investigator’s Award granted by the Crohn’s and Colitis Foundation of America (CCFA) 2012, 2013 Poster of Distinction awarded by the American Gastroenterology Association (AGA) Institute Other Experience 2006- Reviewer for Gastroenterology 2011- Reviewer for Journal of Digestive Diseases 2011- Reviewer for Mucosal Immunology 2012- Reviewer for Plos One 2012- Reviewer for the Israel Science Foundation 2012- Reviewer for the Netherlands Organization for Scientific Research 2013- Reviewer for Inflammatory Bowel Diseases 2014- Reviewer for PeerJ Memberships 2005- Society for Mucosal Immunology

EDUCATION/TRAINING INSTITUTION AND LOCATION University of Newcastle-upon-Tyne, UK Royal College of Physicians, London, UK University of Newcastle-upon-Tyne, UK Royal College of Physicians, London, UK A. Personal Statement I am the Florence and Theodore Baumritter Professor of Medicine and currently the Director of the Division of Endocinology and Metabolism at the James J Peters VA Medical Center. I have been funded continuously by NIH-NIDDK since 1980 and I have published over 450 papers, chapters and books in the area of endocrine cell biology with an emphasis on the thyroid cell and thyroid autoimmunity. I am a member of the American Association of Physicians and recipient of the John B Stanbury Gold Medal of the American Thyroid Association for our work on thyroid physiology and pathophysiology. I am a Past President of the American Thyroid Association. I currently devote my time to research, clinical practice and teaching. We have a long-standing interest in developing an ES cell-based model for studying thyroid development and are in an excellent position to pursue the objectives outlined in our proposal. So far, we have been very successful in generating and characterizing murine ES cell lines and have been able to produce three-dimensional thyroid neofollicles from these ES cells and show that these neofollicles express thyroglobulin. I 139

would not anticipate any major methodological issues that would prevent successful completion of the proposed work and anticipate a paradigm shift that will usher in the time for thyroid cell therapy. B. Positions and Honors 1971-75 Medical Residency, Newcastle-upon-Tyne, United Kingdom. 1975-77 MRC Senior Research Associate, Endocrine Unit, University of Newcastle-upon-Tyne, UK. 1977-79 USPHS Visiting Fellow, ERRB, NICHD, NIH, Bethesda, MD. 1979-82 Assistant Professor of Medicine, Mount Sinai School of Medicine, New York, NY. 1982-86 Associate Professor of Medicine, Mount Sinai School of Medicine, New York, NY. 1986- Professor of Medicine, Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY. Honors: Medical Research Council Training Fellowship (1975-1977).

BIOGRAPHICAL SKETCH NAME Esplugues, Enric EDUCATION/TRAINING INSTITUTION AND LOCATION University of Barcelona University of Barcelona University of Barcelona (Postdoc Fellow) Yale University (Postdoc Fellow) Yale University (Associate Research Scientist) Mount Sinai School of Medicine (Assistant Prof.) A. Personal Statement For the last 15 years, my research has focused on identifying cellular and molecular mechanism that are important for the control of the immune system in humans and mice. I have studied cellular and molecular biological mechanisms relevant to cancer, autoimmunity, infections and different aspects of the immune system affecting their control during pathogenic processes. In my current appointment at Mount Sinai School of Medicine, Department of Medicine/Clinical Immunology Division and as a member of the Immunology Institute, I have recently established an independent research program around the topic Epigenetic Control of Inflammation. B. Positions and Honors 09.1992-10.1997 B.Sc., University of Barcelona 05.1998-10.2003 PhD student, Dept. of Animal Physiology, Immunology Unit. Barcelona, Spain (PI: Dr. Pilar Lauzurica) 11.2003-12.2004 Postdoctoral Fellow, Dept. of Animal Physiology, Immunology Unit. Barcelona, Spain (PI: Dr. Pilar Lauzurica)

EDUCATION/TRAINING INSTITUTION AND LOCATION Louisiana State University University of Wales, Swansea

DEGREE B.S.

YEAR(s) 1997-2001 1999

Boston University

Ph.D.

2003-2008

Washington University in St. Louis

Postdoc

2008-2011

A. Personal Statement My research focuses on data driven computational modeling of the microbiome with predictions that are followed-up experimentally with new or existing technologies. I have pursued aspects of this paradigm for the past 13 years, first as a scientific programmer studying evolutionary genomics, then as a graduate student developing network inference algorithms for large-scale bacterial microarray datasets, and most recently as a postdoctoral fellow and instructor in Dr. Jeffrey Gordon’s lab at Washington University in St. Louis where I applied statistical modeling and systems biology tools to the field of gut microbiome research. I have over 6 years of experience working in the microbiome field, developing experimental advances in gnotobiotics, anaerobic robotics for highthroughput microbial isolation and culturing, improvements in the scale and quality of 16S rRNA amplicon sequencing, and optimized rRNA depletion protocols and data processing pipelines for RNA-Seq metatranscriptomics of both the human and the mouse microbiota. 145

POSITION TITLE Assistant Professor of Medicine (Division of Clinical Immunology) Assistant Professor of Genetics and Genomics FIELD OF STUDY Zoology Study abroad/biology Bioinformatics and Systems Biology Human and mouse gut microbiome

My group’s current work is on modeling the interactions between diet, the microbiota, and host physiology. In addition, we are developing computational and experimental platforms to isolate and identify bacteria that modulate phenotypic changes in mice with an emphasis on the identification of microbes that perturb the immune system. B. Positions and Employment 2001-2002 Research Associate, Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 2002-2003 Scientific Programmer, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 2011-2012 Instructor, Department of Pathology and Immunology, Washington University, St. Louis, MO 2013- Assistant Professor, Department of Medicine, Mt Sinai School of Medicine, New York, NY 2013- Assistant Professor, Department of Genetics and Genomic Sciences, Mt Sinai School of Medicine, New York, NY

BIOGRAPHICAL SKETCH NAME Furtado, Glaucia C. EDUCATION/TRAINING INSTITUTION AND LOCATION University of Santo Amaro, Sao Paulo, Brazil University of Sao Paulo, Sao Paulo, Brazil Advanced Postdoctoral Fellow, New York University A. Personal Statement: I have a long standing interest in autoimmune and inflammatory diseases. My early work showed an important role for IL-2 in Treg function and development. My current research focuses on mucosal inflammation, and lymphoid neogenesis in neonates and adults. B. Positions 1989-1990 Visiting Scientist, National Institutes of Health, Bethesda MD, USA. 1991-1992 Visiting Scientist Yale University School of Medicine, Connecticut CT, USA. 1993-1998 Researcher, Dept. Immunology, University of Sao Paulo SP, Brazil. 1996-1998 Consultant, Techinova-Inovacoes Cientificas, Sao Paulo SP. Brazil. 2003-2014 Assistant Professor, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA 2014Associate Professor, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Awards and Other Professional Activities: 148

EDUCATION/TRAINING INSTITUTION AND LOCATION University of Paris VI, France Ecole Normale Superieure, Paris, France Pasteur Institute and University of Paris VII University of Paris VII INSERM Cochin Inst. Paris Ludwig Institute MSKCC A. Personal Statement I am an immunologist who focuses on human immune responses to cancer in an antigen-specific manner, to define new targets for the development of cancer immunotherapies, ask how these immunotherapies work and why they may fail. My work on tumor antigens such as NY-ESO-1 has established the immunological basis for testing human cancer vaccines in over 40 clinical trials, opening a new field of cancer immunology based on clinical discovery rather than mouse models, with the goal to achieve protective integrated immune responses in the fight against cancer. I am also the Associate Director of the Immunomonitoring Core of Icahn School of Medicine at Mount Sinai Both my existing and future networks of collaborations with local and international academic and industrial partners will help guide and coordinate strategies for the design of correlative studies that aim to uncover the biological and immunological mechanisms underpinning clinical trial results so that one can learn from clinical successes as well as productive failures; to develop and validate biomarkers that can serve as predictors of 151

response; to guide the choice of immunological agent(s) tested and to shape questions being addressed by clinical trials. My work has resulted in 115 publications in high impact peerreviewed journals (most have themselves been cited between 20-500 times by other authors) and nearly 10 patents. My work has also been presented in over 90 international meetings related to immunology and/or cancer, open to both scientists and clinicians. I trained and taught immunological concepts to 8 post-doctoral fellows and 13 technicians. My laboratory has also served as reference for harmonized immunomonitoring for the Cancer Vaccine Collaborative, which has led to the adoption of new standards in serology by other labs. I bring unique expertise in both humoral and cellular immunology against human cancer antigens. My past and proposed research projects are highly relevant to cancer immunology and immunotherapy, bridging laboratory and clinical discovery. I am highly collaborative, and able to foster environment conducive to clinically relevant advances in the field of cancer immunotherapy. As PI or co-Investigator, I have experience with obtaining and renewing grants, from both

private philanthropic and public funding sources. In addition, I successfully administered projects (e.g. staffing, research protections, budget), collaborated with other researchers, and produced many peer-reviewed publications from each project. As a result of these previous experiences, I am aware of the importance of frequent communication among project members and of constructing a realistic research plan, timeline, and budget. In summary, I have a demonstrated record of successful and productive research projects in an area of high relevance for cancer immunotherapy. B. Positions and Honors Positions 2001–2007 Assistant Member, Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 2001–2012 Visiting Investigator, Sloan-Kettering Institute for Cancer Research, New York, NY 2007–2012 Director of Immunological Monitoring, Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY 2007–2012 Associate Member, Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 2010 Adjunct Associate Professor, Roswell Park Cancer Institute, Buffalo, NY 2010 Invited Researcher, Immunology Frontier Research Center, University of Osaka, Japan 2013–present Associate Director of Immunomonitoring Core, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 2013–present Associate Professor (Hematology/Oncology, Immunology), Tisch Cancer Institute,

BIOGRAPHICAL SKETCH NAME Gulko, Percio S. INSTITUTION AND LOCATION Universidade Federal do Rio Grande do Sul (UFRGS), Brazil Medical College of Georgia, Augusta, GA National Institutes of Health, Bethesda, MD A. Personal Statement I am a board-certified rheumatologist, the Chief of Rheumatology and a Professor of Medicine at the Icahn School of Medicine at Mount Sinai. My goal is to identify genes implicated in the regulation of severity and joint damage in rheumatoid arthritis (RA), and to generate new targets and for the development of more effective therapies. My laboratory has been using a) rodent models of autoimmune arthritis to identify and characterize genes involved in the regulation of arthritis severity and joint damage, and b) synovial tissues and cells (fibroblast-like synoviocytes, FLS) from patients with RA to identify genes implicated in cell invasion and articular damage. During the past five years I have been a Principal Investigator in three different NIH R01 grants, all related to RA pathogenesis, and all lead to publications in highly respected peer-reviewed journals. I currently lead the Division of Rheumatology and a growing laboratory at Mount Sinai and have established successful and productive collaborations with other research groups. We have identified several severity and joint damage non-MHC loci. We have also discovered that these arthritis loci operate via the regulation of important phenotypes in disease pathogenesis such as the invasive properties of FLS. We have 155

BIOGRAPHICAL SKETCH NAME Guttman-Yassky, Emma EDUCATION/TRAINING INSTITUTION AND LOCATION Sapir Medical Center, Meir, Kfar Saba, Israel Sackler School of Medicine, Tel-Aviv, Israel Technion-Israel Institute of Technology, Haifa, Israel Rambam Medical Center, Haifa, Israel Memorial Sloan Kettering Cancer Center, New York, NY Bar-Ilan University, Ramat Gan, Israel Weill Cornell Medical College, New York, NY The Rockefeller University, New York, NY A. Personal Statement My research made paradigm-shifting discoveries on the immunologic basis of atopic dermatitis/eczema (AD) in humans, enriching the understanding of the pathophysiology of this common disorder and opening the door to new therapeutic discoveries. I have developed the only comprehensive molecular maps of AD, defining skin differentiation and immune-circuits characterizing this disease. Although linked to both immune and barrier abnormalities, AD’s primary pathogenesis has not been elucidated. This incomplete mechanistic understanding has resulted in lack of effective targeted therapeutics. I am the first to identify in humans a distinct population of T-cells that independently produce IL-22, without co-producing IL-17 (as in mice), framing the concept that in humans Th22 T-cells are distinct from Th17 T-cells. My research revealed that this novel 159

Th22/IL-22 pathway is highly activated in AD lesions, correlating with disease severity, and suggesting a pathogenic role for this axis. My findings conceptualized AD as a Th2/Th22-polarized disease, expanding the prevailing view of AD as a Th2-skewed disease. I associated IL-22 as a potential link between the barrier and immune abnormalities characterizing AD, showing that it inhibits differentiation proteins and induces epidermal hyperplasia, both major characteristics of AD, thus paving the path for potential new therapeutics. I have also designed a clinical trial which has been funded recently by the NIH, utilizing an anti-IL-22 antibody, the first to explore the biological effects of blocking IL-22 on AD disease activity and associated skin pathology. I have also established the reversibility of the AD phenotype and defined a series of

A. Personal Statement I am a Professor of Medicine and Immunology and Director of the Translational Transplant Research Center at the Icahn School of Medicine at Mount Sinai. I spend ~85% of my time performing and or overseeing research efforts in transplantation. I have >18 years of continuous NIH funding including >14 years of R01 funding and ~110 publications on the basic and translational mechanisms underlying transplant rejection and tolerance in mouse models and in human transplant recipients. I am a former K08 recipient, I am PI of an NIH T32 grant for postdocs in transplantation biology, and I have successfully supported more than a dozen K recipients. I have the expertise to train MD and PhD trainees as part of this T32. B. Professional Positions 1984-1987 Intern/Resident, Internal Medicine, Temple University Hospital (Sidney Cohen, M. D., Chairman), Philadelphia, PA 1989-1992 Research Fellow, Dr. Eric G. Neilson's Laboratory , Renal-Electrolyte Section, Department of Medicine, University of Pennsylvania, Philadelphia, PA 1988-1989 Clinical Fellow, Renal-Electrolyte Section , Hospital of the University of Pennsylvania, Philadelphia, PA

BIOGRAPHICAL SKETCH NAME Li, Xiu-Min EDUCATION/TRAINING INSTITUTION AND LOCATION Henan School of Chinese Med. Zhengzhou, China China Academy of Chinese Med. Beijing, China Johns Hopkins University, Baltimore, MD A. Personal Statement As a Professor of Pediatrics and Immunobiology at Pediatric Allergy and Immunology at Icahn School of Medicine at Mount Sinai, I have combined expertise in allergy, molecular biology and medicinal natural products. I am director of Center for Integrative Medicine for Allergies and Wellness. Investigation of safe and effective natural products/compounds and immunotherapy for treating and preventing allergy and asthma is my main research area. My research funds come from NIH, industry, private organization and individual gifts. Over the past 15 years, I have received approximately $14 million in funds for my research. Through a center grant funded by NIH/NCCAM, in which I served as PI, we established a well-equipped botanical chemistry laboratory with instrument and personnel resources needed to characterize anti-allergic/inflammatory compounds in herbal products and to ensure quality and consistency of products used in laboratory and clinical studies. Two natural products developed in my laboratory are classified as US FDA Investigational New Drugs for phase II studies for food allergy and asthma respectively. Through these projects, I established national and international collaborations. I am also faculty of Mount Sinai Graduate School and mentor of masters and PhD students, clinical and research fellows. B. Positions and Honors 166

BIOGRAPHICAL SKETCH NAME Lira, Sergio A. EDUCATION/TRAINING INSTITUTION AND LOCATION Universidade Federal de Pernambuco, Recife, Brazil Universidade Federal de Pernambuco, Recife, Brazil University of California, San Diego Roche Institute for Molecular Biology. Nutley, NJ A. Personal Statement. I am interested in several biological processes related to immune physiology and immune-mediated disease. My research throughout the years has focused on the role of chemokines and their receptors in homeostatic and pathological conditions. I have also studied the biological roles of virus-encoded chemokine receptor oncogenes and chemokine binding proteins. I have studied the role of chemokines and cytokines in lymphoid organogenesis and in autimmune conditions. My most recent studies focus on the biology of innate lymphoid cells and on the role of the microbiome and inflammation in neoplasia. B. Professional Positions: 1980 Research Assistant, Max-Planck Institut fur Biophysikalische Chemie. Gottingen, Germany 1982-1983 Assistant Professor, Physiology DepartmentUniversidade Federal de Pernambuco, Brazil 1985-1988 Research Assistant, Eukaryotic Regulatory Biology Program-University of California, San Diego 1992-1996 Head, Transgenic Unit, Division of OncologyBristol-Myers Squibb Pharmaceutical Res. Inst.

BIOGRAPHICAL SKETCH NAME Masilamani, Madhan EDUCATION/TRAINING INSTITUTION AND LOCATION University of Madras, Chennai, India Pondicherry University, Pondicherry, India University of Konstanz, Konstanz, Germany National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD Positions and Employment 1999-2003 Scientific Assistant/Graduate Student, Department of Biology, University of Konstanz, Germany 2003-2008 Postdoctoral Visiting Fellow, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD Dec 2007 Assistant Professor, Division of Allergy and Immunology, Department of Pediatrics, Mount Sinai School of Medicine, New York, NY Other Experience and Professional Memberships 2004- Member, American Association of Immunology 2008- Member, American Association of Allergy, Asthma and Immunology 2008- Ad-hoc Reviewer: The Journal of Immunology, The Journal of Allergy and Clinical Immunology, PLoS-ONE, Food and Chemical Toxicology, European Journal of Clinical Nutrition Honors 1994 National Merit Scholarship, Ministry of Human Resource and Development, Government of India 1994 Junior Fellowship, Indian Council of Agricultural Research (ICAR), Ministry of Agriculture, Government of India 175

BIOGRAPHICAL SKETCH NAME Mehandru, Saurabh EDUCATION/TRAINING INSTITUTION AND LOCATION University of Delhi, India University of Delhi, India New York University School of Medicine Rockefeller University Mount Sinai School of Medicine A. Personal Statement I am trained as a gastroenterologist with an interest in studying the mucosal immunity. We identified that gastrointestinal CD4+ T cells are preferentially targeted during acute HIV infection and show incomplete reconstitution with sustained and suppressive antiretroviral therapy. These findings have provided an important insight into the role of the GI tract in HIV pathogenesis and vaccine development. To study the generation of HIV specific immune cells in the GI tract, I trained with Dr. Ralph Steinman, Nobel laureate for Medicine in 2011. My laboratory focuses on studying novel pathways of migration of immune cells to the GI tract and on the induction of HIV specific immunity in the intestines. B. Positions and Honors. Positions (while in training programs, above) 2002-2003 Chief Medical Resident, New York University School of Medicine 2006-2007 Research Scientist, Aaron Diamond AIDS Research Center, New York 2009- Adjunct faculty Steinman Laboratory, Rockefeller University, New York 177

POSITION TITLE Assistant Professor in Gastroenterology DEGREE M.B.B.S (MD)

EDUCATION/TRAINING INSTITUTION AND LOCATION University of Paris VII. France Stanford University and University Paris VII. France

DEGREE M.D. Ph.D.

A. Personal Statement: Miriam Merad, M.D.; Ph.D. is a Professor of Oncological science, Medicine (Hem/Onc division) and Immunology and a Member of the Immunology Institute and The Tisch Cancer Institute at the Mount Sinai School of Medicine in New York. Dr. Merad was recruited to Mount Sinai School of Medicine in 2004 and was promoted to the rank of Associate Professor with Tenure in 2007 and to Full Professor in 2010. In 2010 Dr. Merad also became the program leader of the Cancer immunology immunotherapy group at The Tisch Cancer Institute and the director of the Human Immunomonitoring center. Dr. Merad also serves as the Associate Director for the MD PhD program at Mount Sinai Medical School. Dr. Merad’s laboratory studies the mechanisms that regulate the development and function of innate myeloid cells including dendritic cells and macrophages. In 2013, Dr. Merad was the primary organizer of the prestigious Keystone conference on dendritic cell biology and was elected to the “American Society of Clinical Investigation”. She has authored more than 100 primary papers and review articles in high profile journals and obtained extensive NIH funding for her studies on dendritic cells and macrophage biology in mice and humans. B. Positions and Honors 1991-1992 Internship in Internal Medicine.

180

YEAR(s) 1992 2001

FIELD OF STUDY Medicine/ Hematology Immunology

1992-1998 Medical Residency, Internal Medicine. APHP (Hospital of Paris). France 1998-2001 PhD student in Immunology-University Paris VII/ Department of Pathology, Stanford University 2001-2003 Post doctoral Fellow, in ImmunologyDepartment of Pathology, Stanford University Assistant Professor, Department of Gene therapy and Department of Medicine, Mount Sinai School of Medicine. 2007 Associate Professor with Tenure, Department of Gene and Cell Medicine and the Department of Medicine, Mount Sinai School of Medicine. 2009 Program Leader Cancer Immunology Immunotherapy Program, Tisch Cancer Institute, Mount Sinai School of Medicine. 2010-present Professor, Department of Gene and Cell Medicine and the Department of Medicine (Hem/Onc division), Mount Sinai School of Medicine 2012 Professor, Department of Oncological Sciences, Mount Sinai School of Medicine 1999 American Association for Cancer Research 2000 American Association of Immunologists and American Association of Hematology 2005 Member of the steering committee for the “Langerhans Cell Society”

BIOGRAPHICAL SKETCH NAME Moran, Thomas M. EDUCATION/TRAINING INSTITUTION AND LOCATION Northeastern University, Boston, MA Boston University A. Personal Statement Dr. Moran has published widely on immunity to virus infection using both mouse models (ref 1, 2, 4, 6,8,9,11) and studies in or using samples from human subjects (3,5,7, 12,13,15). In addition he has led studies aimed to understand changes that occur in immune functions of women during pregnancy. He served as the Overall director of the NIH funded Center for Investigating Viral Immunity and Antagonism (CIVIA). CIVIA focused on studies of human immunology and infectious disease by advancing technological methodologies, supporting inventive research, serving as a conduit for collaboration and promoting exchange of scientific information. Among other projects, a recent study funded by CIVIA profiled the immune response of patients receiving the live-attenuated influenza virus vaccination. Dr. Moran served as overall PI for the Viral Immunity in Pregnancy study (VIP) that recently concluded. This was a study of changes that occur in women during pregnancy with an emphasis on understanding the enhanced susceptible to infection. Data from the two cohorts of the VIP studyimmune response changes during pregnancy (60 patients) and influenza vaccination during pregnancy (350 patients) were recently published. Dr. Moran is the Director of the Center for Therapeutic Antibody Development (CTAD) at The Icahn School of Medicine at Mount Sinai. The center has been active for more than 15 years and during this time produced many monoclonal 183

POSITION TITLE Professor of Microbiology and Immunology DEGREE BS PhD

MM/YY 1972 1981

FIELD OF STUDY Biological Sciences Immunology/Microbiology

antibodies against various infectious agents and other Immunogens. CTAD has a close collaboration with Medical Research Council-Technology division in London to produce and develop human or humanized monoclonal antibodies. A number of collaborative projects are in progress primarily to develop monoclonal antibodies with therapeutic applications. Technology has been developed and is currently being used by CTAD to produce human monoclonal antibodies by V gene cloning as well as fusion of human B cells expanded by various methods in vitro. B. Positions and Honors 1976-1981 Graduate Studies: Boston University Preceptor: Dr. Michael Bennett; 1981-1983 Post Doctoral Studies: University of Uppsala, Sweden Preceptor: Dr. Hans Wigzell 1983-1985 Post Doctoral Studies: Mount Sinai School of Medicine Preceptor: Dr. Constantin Bona 1986-1989 Assistant Research Professor Department of Microbiology, Mount Sinai School of Medicine 1990-1993 Associate Research Professor Department of Microbiology, Mount Sinai School of Medicine 1990-2012 Director, Center for Therapeutic Antibody Development, Mount Sinai School of Medicine 1993-2005 Associate Professor, Department of Microbiology, Mount Sinai School of Medicine

BIOGRAPHICAL SKETCH NAME Murphy, Barbara T. EDUCATION/TRAINING INSTITUTION AND LOCATION The Royal College of Surgeons The Royal College of Physicians The Royal College of Physicians A. Personal Statement The focus of my research has been in transplant immunology and transplant genomics for which I have had NIH funding for 19 years. My research focuses on the role of genetics and genomics in the prediction of clinical and pathological outcomes in transplantation. I am the PI of a large multicenter grant entitled “Genomics of Chronic Allograft Rejection” (GoCAR). GoCAR is one of the largest prospective studies in transplantation brining together investigators in seven institutions and two continents. B. Positions and Honors Internship and Residency: July1989- June 1990: Internship, Beaumont Hospital, Dublin, Ireland. July 1990 - June1992: Residency Rotation, Beaumont Hospital, Dublin. July 1992-June 1993: Clinical Nephrology, Fellow, Beaumont Hospital, Dublin. July 1993 -May 1997: Nephrology Fellow, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston Hospital Appointments: 1997 - 2005 Director of Transplant Nephrology, Mount Sinai Hospital, New York 186

POSITION TITLE Professor DEGREE MB BAO MRCPI FRCPI

MM/YY 1989 1992 1998

FIELD OF STUDY Medicine Medicine Medicine

2003 - 2004 Interim Chief of Nephrology, Mount Sinai School of Medicine, New York 2004 - 2013 Chief, Division of Nephrology, Mount Sinai School of Medicine, New York 2012 - Chair, Department of Medicine, Mount Sinai School of Medicine, New York Academic Appointments: 1997 – 2003 Assistant Professor of Medicine, Mount Sinai School of Medicine, New York 2003- 2007 Associate Professor of Medicine, Mount Sinai School of Medicine, New York 2008 Professor of Medicine, Mount Sinai School of Medicine, New York 2011 - 2012 Dean for Clinical and Population based Research 2011 - 2012 Director of Conduits, The Institute for Translational Science 2012 - Chair Department of Medicine, Icahn School of Medicine at Mount Sinai 2013 - Dean for Clinical Integration and Population Based Health Honors and Awards 1994 Young Investigator Award, American Society of Transplant Physicians. 1996 Young Investigator Award, American Society of

BIOGRAPHICAL SKETCH NAME Ochando, Jordi EDUCATION/TRAINING INSTITUTION AND LOCATION University of Alicante, Spain De Montfort University, Leicester, England Mount Sinai School of Medicine, New York A. Personal Statement My laboratory investigates the origin, development and immune regulatory function of myeloid derived suppressive cells (MDSC). As negative regulators of the immune response, MDSC represent a novel therapeutic approach for manipulating the immune system toward tolerance or immunity. Since MDSC have considerable relevance to the crucial problem as why a growing tumor cannot be rejected despite the recognition of tumor associated antigens, our laboratory investigates the immunological mechanisms of tumor acceptance mediated by MDSC, which can be exploited to prevent allograft rejection in transplantation. I have a broad background in transplant immunology with documented research experience. During my postdoctoral research at Mount Sinai School of Medicine, I published several manuscripts in high impact factor journals including two Nature Immunology manuscripts as fist author. Specifically, I investigated the suppressive function of regulatory T cells in transplantation using an experimental model of heart transplant in mice, and identified that alloantigen-presenting plasmacytoid dendritic cells participate Treg development and mediate tolerance. As principal investigator I laid the groundwork for my current research by identifying monocytic

189

POSITION TITLE Assistant Professor of Medicine DEGREE B.Sc MPhil/PhD Postdoctoral

MM/YY 06-98 06-02 01-06

FIELD OF STUDY Biology Immunology Transplant Immunology

MDSC as critical components of the tolerogenic signature during the immune response to an allograft. This work was published in The Journal of Clinical Investigation in 2010. My laboratory is now focused in providing new insights into the mechanisms by which MDSC inhibit T cell responses and promote tolerance, and our current work it is being reviewed in the prestigious journal Immunity. We believe that understanding how myeloid derived suppressor cells inhibit T cell responses and promote regulatory T cell development in vivo will open new avenues for therapeutic intervention either by inhibiting their function (i.e. in cancer patients), or by enhancing their suppressive effects and promoting their expansion (i.e. in transplant recipients). As the scientific director of the Flow Cytometry Shared Research Facility at Mount Sinai School of Medicine I am also leading a team that provides state of the art technology and professional expertise to support planning of experiments, data acquisition, and analysis of flow cytometry experiments. Flow cytometry allows simultaneous multiparametric analysis and fluorescence activated cell sorting (FACS) of thousands of cells per second, which enables researchers to investigate complex cellular processes in a variety of models comprising healthy and disease states. It is therefore routinely used in the diagnosis of

health disorders, especially blood cancers, but has many other applications in both research and clinical practice. With this in mind, our mission is to provide the necessary instrumentation and knowledge for cell cytofluorimetric analysis and sterile sorting of specific cell types to the Immunology Institute investigators. B. Positions and Honors Positions and Employment: 2002-2006 Postdoctoral Fellow, Mount Sinai School of Medicine, NY 2006-2007 Academic Instructor, Mount Sinai School of Medicine, NY 2007-2010 Visiting Scientist, Mount Sinai School of Medicine, NY 2007-2010 Staff Scientist, Spanish Institutes of Health, Spain 2011- Assistant Professor, Mount Sinai School of Medicine, NY 2012- Scientific Director of Flow Cytometry SRF, Mount Sinai School of Medicine, NY Other Experience and Professional Memberships: 2007 Member of the Transplantation Society 2008 Member of the European Society for Organ Transplantation 2010 Member of the American Society of Transplantation Honors and Awards: 1998 De Montfort University PhD Fellowship 2002 Federation of Clinical Immunologists travel Award 2005 AST Young Investigator award 2006 AST International Investigator Award 2011 AST Basic Sciences Faculty Development Award

BIOGRAPHICAL SKETCH NAME Sampson , Hugh A. EDUCATION/TRAINING INSTITUTION AND LOCATION Hamilton College [Clinton, NY] S.U.N.Y. at Buffalo Medical School [Buffalo, NY] Children's Memorial Hosp [Northwestern; Duke University Medical Center [Durham, NC] Chicago, IL] A. Personal statement I am a pediatrician, pediatric allergist and immunologist. I have been involved in both basic and translational research on food allergy for nearly 30 years and have extensive experience in immunophenotyping. In basic studies by my group, we have developed and utilized murine models to investigate immune mechanisms of food-induced anaphylaxis and developed novel therapeutic strategies; e.g. engineered recombinant peanut protein vaccine. In human studies, we have investigated immune mechanisms of food-induced symptoms in children with atopic dermatitis, asthma, anaphylaxis and eosinophilic esophagitis, and developed novel approaches to better diagnose food allergy. We have characterized over 30 allergenic proteins in various food allergens, work that has contributed to a better understanding of allergic responses to food, better diagnostic assays and novel therapeutic approaches. I have conducted several clinical trials investigating therapeutic strategies to treat food allergy. I am the PI on the NIH-funded Consortium for Food Allergy Research [6 universities], which has investigated the use of egg oral immunotherapy, peanut sublingual immunotherapy, and rectal administration of a heatkilled E coli-containing re-engineered, recombinant peanut proteins (Ara h 1, 2 and 3). I currently direct the AADCRC 192

POSITION TITLE Professor of Pediatrics DEGREE B.A. M.D. Residency Fellowship

YEAR(s) 1971 1975 1978 1980

FIELD OF STUDY Biology Medicine Pediatrics Allergy/Immunology

program project on milk allergy, which has been investigating the administration of baked-milk products and milk oral immunotherapy with or without omalizumab. I have served on numerous expert panels, including the NIH Expert Panel on Food Allergy, and chaired an NIAID Expert Panel on the Guidelines for the Diagnosis & Management of Food Allergy. I have served as the Director of the General Clinical Research Center at Johns Hopkins and I am currently Director of Conduits, Mount Sinai’s CTSA. B. Positions and Honors Positions and Employment 1980 to 1986 Assistant to Associate Professor of Pediatrics, Duke Univ. School of Medicine 1983 to 1986 Associate Director, General Clinical Research Center, Duke University 1986 to 1991 Associate Professor of Pediatrics, Johns Hopkins Univ. School of Medicine 1988 to 1997 Director, Pediatrics Clinical Research Center, Johns Hopkins University 1991 to 1997 Professor of Pediatrics, Johns Hopkins University School of Medicine 1997 to present Professor of Pediatrics & Immunobiology, Mount Sinai School of Medicine

BIOGRAPHICAL SKETCH NAME Sikora, Andrew, Gregory EDUCATION/TRAINING INSTITUTION AND LOCATION Yale University, New Haven, CT Albert Einstein College of Medicine, Bronx, NY Albert Einstein College of Medicine, Bronx, NY A. Personal Statement As a fellowship-trained surgical oncologist and immunologist with experience in both basic laboratory science and clinical trials, my unique portfolio of expertise provides the background necessary to mentor graduate students with an interest in translational research. I have extensive training in, and publications relating to, head and neck cancer, basic immunology, inflammation, cancer immunotherapy, and translational cancer research. I am the PI of multiple clinical trials, including trials related to HPV-mediated squamous cell carcinoma, and immunology of head and neck cancer. I also run a basic/translational laboratory focused on understanding mechanisms of tumor-induced inflammation and immunosuppression and harnessing targeted therapy approaches to improve anti-cancer immunotherapy. Mentoring graduate and medical students and postdoctoral fellows has been one of the great pleasures of my career thus far, and I am proud of the many students who have won research prizes and obtained competive grants and fellowships to support their work - including awards from the NCI, the German Cancer Aid Foundation, and the Doris Duke and Howard Hughes research foundations. B. Positions and Honors Positions and Employment 198

BIOGRAPHICAL SKETCH NAME Ting, Adrian T. EDUCATION/TRAINING INSTITUTION AND LOCATION Luther College, Decorah, IA Mayo Graduate School, Rochester, MN Massachusetts General Hospital, Boston, MA A. Personal Statement My lab is interested in the role of ubiquitination and how this post-translational modification affects cellular survival and death, as well as inflammatory signaling pathways. One focus of our studies is the role played by ubiquitination of the TNFR1 signaling molecule RIP1. We made the discovery that noncanonical K63-linked polyubiquitination of RIP1, or the lack thereof, determines whether cell survival or apoptotic cell death ensues in response to TNF. Thus, ubiquitination of RIP1 serves to function as an early cell death checkpoint in TNF signaling. More recently, we discovered that ubiquitination also has a significant role in regulating a novel form of cell death that is caspaseindependent known as necroptosis or programmed necrosis. Specifically, we made the observation that Caspase 8 has a prosurvival function (contrary to its well established role in causing apoptosis) by inhibiting necroptosis via the cleavage and degradation of CYLD. CYLD is a tumor suppressor and is a deubiquitinating enzyme that preferentially removes noncanonical K63-linked polyubiquitin chains from target proteins including RIP1. Removal of ubiquitin chains from RIP1 by CYLD is required for necrotic cell death to occur. Apoptotic cell death is generally thought of to be anti-inflammatory whereas necrotic cell death is thought of to be inflammatory. Since dysregulation of TNF underlies multiple inflammatory diseases, development 201

BIOGRAPHICAL SKETCH NAME Xiong, Huabao EDUCATION/TRAINING INSTITUTION AND LOCATION Southeast University School of Medicine, Nanjing, China Niigata University School of Medicine, Niigata, Japan A. Personal Statement The studies we propose here are a direct extension of our recent findings. We have demonstrated that IRF8 deficiency in conventional as well as T cell-specific IRF8 knockout mice dominantly leads to efficient Th17 cell differentiation without affecting either the Th1 or Th2 cell lineages. Indeed, IRF8 deficiency results in more severe intestinal inflammation with an enhanced Th17 phenotype in an experimental model of colitis. Interestingly, the enhancement of IL-17+TNFa+ Th17 cell subpopulation was significantly increased in IRF8 deficient mice and correlated with the exacerbation of colitis in RAG-/- mice reconstituted with IRF8-/- T cells. These findings define a novel Th17 cell subpopulation and highlight the importance of IL17+TNFa+ Th17 cells in the development of colitis. My laboratory has extensive expertise in infection models, transcriptional regulation, cytokine biology, macrophage and T cell biology, as well as different murine colitis models. Thus I have the knowledge and experience required to administer this grant. B. Positions and Honors Positions and Employment 1989 – 1992 Assistant Professor, National Center for Sexually Transmitted Diseases, Chinese Academy of Medical Sciences, China 207

A. Personal Statement I have been steadily pursuing a research program that aims to study innate immunity and cell death pathways towards the discovery of novel biological therapeutics for inflammatorymediated immune disorders. The primary focus of my research program is to elucidate the molecular mechanisms and roles of cytosolic pattern recognition receptors of the Nod-like receptor (NLR) family in host defense, chronic inflammation and cancer. Several established approaches, ranging from genetically modified mouse models to biochemistry and cellular immunology methods, are used in my laboratory to gain insight into the mechanisms that govern host-microbiota and hostpathogen interactions in health and disease. As a postdoctoral fellow at McGill University, I have particularly investigated the functions of various apoptosis effectors in infection, inflammatory bowel diseases and colorectal cancer. My broad experience allows me to tackle questions about the molecular mechanisms that regulate inflammatory responses and apoptosis in the cell. In addition, I have a demonstrated track record of collaborative, successful, highly productive, and focused research projects of the hand. My previous experiences 210

POSITION TITLE Assistant Professor FIELD OF STUDY Animal Biology (Microbiology and Immunology) Biochemistry, Cell and Molecular Biology Cellular and Molecular Biology Immunology and Microbiology

EDUCATION/TRAINING INSTITUTION AND LOCATION Hofstra University SUNY of NY at Buffalo/University of Wisconsin

DEGREE B.A. Ph.D.

Professional Experience 1972-75 Pre-doctoral Trainee, Immunobiology Research Center and Department of Genetics, University of Wisconsin. 1974-77 Post-doctoral Fellow, Department of Medicine, University of Innsbruck, Austria 1977-80 Instructor, National Tissue Typing Laboratory and WHO Collaborating Laboratory, University of Munich, Germany. 1980-86 Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA. 1986-88 Associate Professor of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA. 1988-96 Associate Professor of Medicine and Microbiology, Mount Sinai School of Medicine, New York, NY. 1996- present Professor of Medicine, Mount Sinai School of Medicine, New York, NY. 1997- present Professor, Immunology Institute, Mount Sinai School of Medicine 1998- present Professor of Microbiology, Mount Sinai School of Medicine Mount Sinai School of Medicine 1999- present Professor, Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine 1999 -present Associate Dean for Medical Student Research Other Professional Activities: 217